Anesthetic compounds and methods of making and using same to treat or prevent pain symptoms

ABSTRACT

The present disclosure provides compounds useful as anesthetics, such as topical anesthetics, of general formula (I):wherein:R1 is H, —OMe, Me, or one or more electron withdrawing groups;R2 and R3 are each independently H or alkyl or, taken together, form a 4- to 8-membered heterocyclic ring with the adjacent nitrogen atom;R4 is H or alkyl;R5 is H or one or more electron donating groups; andn is 1 to 4.The present disclosure further provides compositions comprising a therapeutically effective amount of a compound of general formula (I), and methods of treating or preventing pain in a subject by administering (e.g., topically applying) such compositions to the subject.

PRIORITY CLAIM

This application claims priority to U.S. Provisional Patent Application Ser. No. 63/317,868, filed on Mar. 8, 2022, the entire contents of which are incorporated herein by reference.

FIELD

The present disclosure provides compounds useful as anesthetic agents, methods of making same, compositions comprising same, and methods of treating or preventing pain using same.

BACKGROUND

Anesthetic agents are commonly used to treat or prevent pain sensations. However, certain classes of anesthetics encourage overuse, abuse, and/or overprescribing. Other agents are potent, but provide low bioavailability for example when administered topically.

A need persists for improved anesthetic agents, especially agents that are effective when applied topically to skin of a subject.

SUMMARY

In one embodiment, the present disclosure provides a compound of formula (I):

wherein:

-   -   R₁ is H, —OMe, Me, or one or more electron withdrawing groups;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl;     -   R₅ is H or one or more electron donating groups; and     -   n is 1 to 4.

In other embodiments, the present disclosure provides a compound of formula (II):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, CF₃, and OCF₃;     -   R₂ and R₃ are each independently H or alkyl;     -   Alk is an aliphatic carbon group consisting of 1 to 6 carbon         atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (III):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, CF₃, and OCF₃;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (IV):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more amino, aryl, acylamido, acyloxy, alkoxy or         alkyl electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (V):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In other embodiments, the present disclosure provides a compound of formula (VI):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, —OMe, or methyl;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In other embodiments, the present disclosure provides a compound of formula (VII):

wherein:

-   -   R_(1a) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R_(1b) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1c) is H, Cl, F, or —OMe;     -   R_(1d) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1e) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl; and     -   R₅ is H or one or more electron donating groups.

In other embodiments, the present disclosure provides a compound of formula (VIIIa):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIb):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIc):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIId):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIe):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIf):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIg):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIh):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIi):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIj):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIk):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIm):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (VIIIn):

wherein:

-   -   A=C or N;     -   R₄=Alkyl;     -   R₅=O-Alkyl;     -   when A=C, R₁₀=R₁₁=H; or when A=N, R₁₀=Alkyl and R₁₁=null; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In other embodiments, the present disclosure provides a compound of formula (IX):

wherein:

-   -   R₁=H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl;         m-trifluoromethoxy; m-trifluoromethyl, p-chloro; 2,5-dichloro;         3-chloro-4-fluoro; 2-fluoro-3-chloro; or o-trifluoromethyl.

In other embodiments, the present disclosure provides a compound of formula (X):

-   -   R₁=H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl;         m-trifluoromethoxy; m-trifluoromethyl, p-chloro; 2,5-dichloro;         3-chloro-4-fluoro; 2-fluoro-3-chloro; or o-trifluoromethyl.

In other embodiments, the present disclosure provides a compound of formula (XI):

wherein:

-   -   R₁=H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl;         m-trifluoromethoxy; m-trifluoromethyl, p-chloro; 2,5-dichloro;         3-chloro-4-fluoro; 2-fluoro-3-chloro; or o-trifluoromethyl.

In other embodiments, the present disclosure provides a compound of formula (XII):

wherein:

-   -   R₁=H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl;         m-trifluoromethoxy; m-trifluoromethyl, p-chloro; 2,5-dichloro;         3-chloro-4-fluoro; 2-fluoro-3-chloro; or o-trifluoromethyl.

In other embodiments, the present disclosure provides a compound of formula (XIII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XIII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XIII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XIV):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XV):

wherein:

In other embodiments, the present disclosure provides a compound of formula (XVI):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XVII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XVIII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XIX):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XX):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XXI):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XXII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XXIII):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a compound of formula (XXIV):

wherein:

-   -   R₈=NH₂, NH(Me), N(Me)₂,

In other embodiments, the present disclosure provides a composition comprising a compound of any one of formulas (I) to (XXIV).

In other embodiments, the present disclosure provides a method of treating or preventing pain in a subject, the method comprising topically applying the composition comprising a compound of any one of formulas (I) to (XXIV) to skin of the subject proximal to perceived pain or expected pain.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a representative synthetic route for producing compounds of formula (I).

FIG. 2 shows a representative synthetic route for producing compounds of formula (II).

FIG. 3 shows a representative synthetic route for producing compounds of formula (III).

FIG. 4 shows a representative synthetic route for producing compounds of formula (IV).

FIG. 5 shows a representative synthetic route for producing compounds of formula (V).

FIG. 6 shows a representative synthetic route for producing compounds of formula (VI).

FIG. 7 shows a representative synthetic route for producing compounds of formula (VII).

FIG. 8 shows a representative synthetic route for producing compounds of formula (VIIIa).

FIG. 9 shows a representative synthetic route for producing compounds of formula (VIIIb).

FIG. 10 shows a representative synthetic route for producing compounds of formula (VIIIc).

FIG. 11 shows a representative synthetic route for producing compounds of formula (VIIId).

FIG. 12 shows a representative synthetic route for producing compounds of formula (VIIIe).

FIG. 13 shows a representative synthetic route for producing compounds of formula (VIIIf).

FIG. 14 shows a representative synthetic route for producing compounds of formula (VIIIg).

FIG. 15 shows a representative synthetic route for producing compounds of formula (VIIIh).

FIG. 16 shows a representative synthetic route for producing compounds of formula (VIIIi).

FIG. 17 shows a representative synthetic route for producing compounds of formula (VIIIj).

FIG. 18 shows a representative synthetic route for producing compounds of formula (VIIIk).

FIG. 19 shows a representative synthetic route for producing compounds of formula (VIIIm).

FIG. 20 shows a representative synthetic route for producing compounds of formula (VIIIn).

FIG. 21 shows a representative synthetic route for producing compounds of formula (IX).

FIG. 22 shows a representative synthetic route for producing compounds of formula (X).

FIG. 23 shows a representative synthetic route for producing compounds of formula (XI).

FIG. 24 shows a representative synthetic route for producing compounds of formula (XII).

FIG. 25 shows a representative synthetic route for producing compounds of formula (XIII).

FIG. 26 shows a representative synthetic route for producing compounds of formula (XIV).

FIG. 27 shows a representative synthetic route for producing compounds of formula (XV).

FIG. 28 shows a representative synthetic route for producing compounds of formula (XVI).

FIG. 29 shows a representative synthetic route for producing compounds of formula (XVII).

FIG. 30 shows a representative synthetic route for producing compounds of formula (XVIII).

FIG. 31 shows a representative synthetic route for producing compounds of formula (XIX).

FIG. 32 shows a representative synthetic route for producing compounds of formula (XX).

FIG. 33 shows a representative synthetic route for producing compounds of formula (XXI).

FIG. 34 shows a representative synthetic route for producing compounds of formula (XXII).

FIG. 35 shows a representative synthetic route for producing compounds of formula (XXIII).

FIG. 36 shows a representative synthetic route for producing compounds of formula (XXIV).

DETAILED DESCRIPTION

The present disclosure provides compounds useful as anesthetic agents, for example to treat or prevent pain when applied topically to skin of a subject, and methods of making such compounds and using such compounds to treat or prevent pain.

1. Anesthetic Compounds

The present disclosure provides compounds of formula (I):

wherein:

-   -   R₁ is H, alkyl, alkoxy, or one or more electron withdrawing         groups;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl;     -   R₅ is H or one or more electron donating groups; and     -   n is 1 to 4.

The present disclosure also provides salts of compounds of formula (I), which may be prepared for example by contacting a neutral compound of formula (I) with an acid (e.g., hydrochloric acid) to form a salt (e.g., a hydrochloride salt) of the compound of formula (I). A suitable salt of a compound of formula (I) is a salt of a mineral or organic acid. Suitable mineral acids include hydrochloric, hydrobromic, hydroiodic, nitric or sulfuric acid. A suitable organic acid is, for example, an organic achiral acid such as acetic, trifluoroacetic, oxalic or p-toluenesulfonic acid, or an organic chiral acid such as L-tartaric acid, dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid.

The present disclosure also provides hydrates of compounds of formula (I).

In some embodiments, R₁ is selected from the group consisting of: H, alkyl, alkoxy, and electron withdrawing groups. In some embodiments, only one R₁ group is present and may be at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, two to five R₁ groups are present, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups, and each R₁ group located at any combination of the ortho-, meta-, and para-positions of the aryl ring. For example and without limitation, two R₁ groups may be present in a compound of formula (I) consistent with the present disclosure, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In other embodiments, three R₁ groups are present, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups. In still other embodiments, four R₁ groups are present. In other embodiments, five R₁ groups are present, and each R₁ group is independently selected from the group consisting of H, alkyl, alkoxy, and electron withdrawing groups.

When R₁ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₁ is alkoxy, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₁ is an electron withdrawing group, the electron withdrawing group may be a halogen, a halogenated alkyl group, or a halogenated alkoxy group. For example and without limitation, the electron withdrawing group may be a halgoen, a halogen-substituted alkyl, a halogen-substituted alkoxyl, a perhaloalkyl, or a perhaloalkoxyl, fluoro, In some embodiments, each electron withdrawing group is independently selected from chloro, bromide, iodide, halomethyl, dihalomethyl, trihalomethyl, halomethoxyl, dihalomethoxyl, and trihalomethoxyl. In some embodiments, each electron withdrawing group is independently selected from the group consisting of fluoro, chloro, trifluoromethyl, and trifluoromethoxyl.

Each R₂ and R₃ are each independently H or alkyl or, taken together, form a 4- to 8-membered heterocyclic ring with the adjacent nitrogen atom. In some embodiments, R₂ is H while R₃ is alkyl. In some embodiments, both R₂ and R₃ are alkyl. When R₂ and/or R₃ are alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

In some embodiments, R₂ and R₃ are covalently connected to form, with the adjacent nitrogen atom, a heterocyclic ring. The heterocyclic ring may include one to three nitrogen atoms and a total of four to eight atoms in the ring. The heterocyclic ring may be unsubstituted or substituted, for example with an alkyl or alkoxyl group. For example and without limitation, R₂ and R₃ may be covalently connected and include a total of five carbon atoms to form a piperidinyl ring including the nitrogen atom adjacent to R₂ and R₃. In other embodiments, R₂ and R₃ may, together, have a general formula —(CH₂)_(p)N(R₇)(CH₂)_(q)—, wherein p is 1 to 4, q is 1 to 4, p and q combined total 3 to 8, and R₇ is H or alkyl. When R₇ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₄ is H or alkyl. When R₄ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is H or one or more electron donating groups. When R₅ is one or more electron donating groups, R₅ may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₅ may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each electron donating group may be independently selected from alkyl and alkoxyl. When R₅ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When R₅ is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

The number of methylene groups (n) in compounds of formula (I) may be 1 to 4. In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4.

Some example compounds of formula (I) are provided in Table 1 below.

TABLE 1 Example Compounds of Formula (I) Compound R₁ R₂ R₃ R₄ R₅ R₇ n p q 2290 H Me Me Me p-OMe n/a 2 n/a n/a 2291 m-Cl Me Me Me p-OMe n/a 2 n/a n/a 2292 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2293 o-OMe Me Me Me p-OMe n/a 2 n/a n/a 2294 p-OMe Me Me Me p-OMe n/a 2 n/a n/a 2295 o-Me Me Me Me p-OMe n/a 2 n/a n/a 2296 m-OCF₃ Me Me Me p-OMe n/a 2 n/a n/a 2297 m-CF₃ Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2298 2-Cl Me Me Me p-OMe n/a 2 n/a n/a 5-Cl 2299 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-F 2300 2-F Me Me Me p-OMe n/a 2 n/a n/a 3-Cl 2301 o-CF₃ Me Me Me p-OMe n/a 2 n/a n/a 2302 H H H Me p-OMe n/a 2 n/a n/a 2303 H —(CH₂)₅— Me p-OMe n/a 2 n/a n/a 2304 H —(CH₂)_(p)N(R₇)(CH₂)_(q)— Me p-OMe Me 2 2 2

Referring now to FIG. 1 , compounds consistent with formula (I) can be synthesized by, for example, acylating anilines 8_(I) with bromoacetyl bromide to form α-bromoamido intermediates 9_(I). Intermediates 11_(I) can be formed by alkylating anilines 10_(I) with β-haloamines 12_(I) in the presence of base. Combining intermediates 11_(I) with the α-bromoamido intermediates 9_(I) in the presence of base yields compounds of formula (I).

The present disclosure also provides compounds of formula (II):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, halogenated alkyl, and halogenated         alkoxyl;     -   R₂ and R₃ are each independently H or alkyl;     -   Alk is an aliphatic carbon group consisting of 1 to 6 carbon         atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In compounds of formula (II), EWG is one or more electron withdrawing groups each independently selected from the group consisting of: Cl, F, halogenated alkyl, and halogenated alkoxyl. For example and without limitation, EWG may in some embodiments be a single electron withdrawing group located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EWG is two or more electron withdrawing groups located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

Each EWG may independently be selected from the group consisting of chloro, fluoro, halogenated alkyl, and halogenated alkoxyl. The halogenated alkyl may be monohaloalkyl, dihaloalkyl, trihaloalkyl, or perhaloalkyl and may have 1 to 6 carbon atoms (i.e., C₁₋₆ haloalkyl). The haloalkyl electron withdrawing group may be saturated or unsaturated. The halogenated alkyl may be branched, linear, or cyclic. In some embodiments, the electron withdrawing group is trifluoromethyl. The halogenated alkoxyl may be monohaloalkoxyl, dihaloalkoxyl, trihaloalkoxyl, or perhaloalkoxyl and may have 1 to 6 carbon atoms (i.e., C₁₋₆ haloalkoxyl). The haloalkoxyl electron withdrawing group may be saturated or unsaturated. The halogenated alkoxyl may be branched, linear, or cyclic. In some embodiments, the electron withdrawing group is trifluoromethoxyl.

Each R₂ and R₃ is independently H or alkyl. When R₂ and/or R₃ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

EDG is one or more alkoxy or alkyl electron donating groups. EDG may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EDG may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each EDG may be independently selected from alkyl and alkoxyl. When EDG is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

Some example compounds of formula (II) are provided in Table 2 below.

TABLE 2 Example Compounds of Formula (II) Compound EWG R₂ R₃ Alk EDG R₇ n p q 2290 H Me Me Me p-OMe n/a 2 n/a n/a 2291 m-Cl Me Me Me p-OMe n/a 2 n/a n/a 2292 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2293 o-OMe Me Me Me p-OMe n/a 2 n/a n/a 2294 p-OMe Me Me Me p-OMe n/a 2 n/a n/a 2295 o-Me Me Me Me p-OMe n/a 2 n/a n/a 2296 m-OCF₃ Me Me Me p-OMe n/a 2 n/a n/a 2297 m-CF₃ Me Me Me p-OMe n/a 2 n/a n/a p-Cl 2298 2-Cl Me Me Me p-OMe n/a 2 n/a n/a 5-Cl 2299 m-Cl Me Me Me p-OMe n/a 2 n/a n/a p-F 2300 2-F Me Me Me p-OMe n/a 2 n/a n/a 3-Cl 2301 o-CF₃ Me Me Me p-OMe n/a 2 n/a n/a 2302 H H H Me p-OMe n/a 2 n/a n/a 2303 H —(CH₂)₅— Me p-OMe n/a 2 n/a n/a 2304 H —(CH₂)_(p)N(R₇)(CH₂)_(q)— Me p-OMe Me 2 2 2

Referring now to FIG. 2 , compounds consistent with formula (II) can be synthesized by, for example, acylating alkylanilines 8_(II) with bromoacetyl bromide to form α-bromoamido intermediates 9_(II). Intermediates 11_(II) can be formed by alkylating anilines 10_(II) with β-haloamines 12_(II) in the presence of base. Combining intermediates 11_(II) with the α-bromoamido intermediates 9_(II) in the presence of base yields compounds of formula (II).

The present disclosure also provides compounds of formula (III):

wherein:

-   -   EWG is one or more electron withdrawing groups selected from the         group consisting of: Cl, F, CF₃, and OCF₃;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more alkoxy or alkyl electron donating groups.

In compounds of formula (III), EWG is one or more electron withdrawing groups each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, and trifluoromethoxy. For example and without limitation, EWG may in some embodiments be a single electron withdrawing group that is chloro, fluoro, trifluoromethyl, or trifluoromethoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EWG is two or more electron withdrawing groups independently selected from chloro, fluoro, trifluoromethyl, and trifluoromethoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

EDG is one or more alkoxy or alkyl electron donating groups. EDG may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, EDG may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each EDG may be independently selected from alkyl and alkoxyl. When EDG is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

Some example compounds of formula (III) are provided in Table 3 below.

TABLE 3 Example Compounds of Formula (III) Compound EWG R₈ Alk EDG R₇ m n p q 2290 H —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2302 H —NH₂ Me p-OMe n/a n/a 2 n/a n/a 2303 H

Me p-OMe n/a 5 2 n/a n/a 2304 H

Me p-OMe Me n/a 2 2 2

Referring now to FIG. 3 , compounds consistent with formula (III) can be synthesized by, for example, acylating alkylanilines 8_(III) with bromoacetyl bromide to form α-bromoamido intermediates 9_(III). Intermediates 11_(III) can be formed by alkylating anilines 10_(III) with β-haloamines 12_(III) in the presence of base. Combining intermediates 11_(III) with the α-bromoamido intermediates 9_(III) in the presence of base yields compounds of formula (III).

The present disclosure further provides compounds of formula (IV):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6;     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms; and     -   EDG is one or more amino, aryl, acylamido, acyloxy, alkoxy or         alkyl electron donating groups.

In compounds of formula (IV), R₁ is H or one or more substituents each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy. For example and without limitation, R₁ may in some embodiments be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy, or methoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₁ is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

EDG is one or more amino, aryl, acylamido, acyloxy, alkoxy or alkyl electron donating groups. EDG may be a single electron donating substituent in the ortho-, meta-, or para-position of the aryl ring. In some embodiments, the single EDG substituent is at the ortho-position of the aryl ring. In other embodiments, the single EDG substituent is at the para-position of the aryl ring. In other embodiments, EDG may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. In some embodiments, two EDG substituents are at the two ortho-positions of the aryl ring. In other embodiments, one EDG substituent is at the ortho-position and a second same or different EDG substituent is at the para-position of the aryl ring. In other embodiments, one EDG substituent is at one ortho-position of the aryl ring and a second same or different EDG substituent is at the other ortho-position of the aryl ring. In some embodiments, one EDG substituent is at one ortho-position of the aryl ring, a second same or different EDG substituent is at the other ortho-position of the aryl ring, and a third same or different EDG substituent is at the para-position of the aryl ring.

Each EDG may be independently selected from amino, aryl, acylamido, acyloxy, alkoxy or alkyl. When EDG is amino, the amino group may be —NH₂, —N(H)Alk, or —N(Alk)₂, with each Alk being an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is aryl, the aryl substituent may be substituted or unsubstituted. The aryl substituent may be heteroatomic, such as a pyridine ring, a pyrazine ring, or a triazine ring that is substituted or unsubstituted. When EDG is acylamido, the acylamido group has a general formula of —N(H)COR₉, with R₉ being substituted or unsubstituted alkyl. When EDG is acyloxy, the acyloxy group has a general formula of —OC(O)R₉, with R₉ being substituted or unsubstituted alkyl. When EDG is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When EDG is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, EDG is para-alkoxy, such as para-methoxy, para-ethoxy, or para-propoxy.

Some example compounds of formula (IV) are provided in Table 4 below.

TABLE 4 Example Compounds of Formula (IV) Com- pound R₁ R₈ Alk EDG R₇ m n p q 2290 H —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me p-OMe n/a n/a 2 n/a n/a 2302 H —NH₂ Me p-OMe n/a n/a 2 n/a n/a 2303 H

Me p-OMe n/a 5 2 n/a n/a 2304 H

Me p-OMe Me n/a 2 2 2

Referring now to FIG. 4 , compounds consistent with formula (IV) can be synthesized by, for example, acylating alkylanilines 8_(IV) with bromoacetyl bromide to form α-bromoamido intermediates 9_(IV). Intermediates 11_(IV) can be formed by alkylating anilines 10_(IV) with β-haloamines 12_(IV) in the presence of base. Combining intermediates 11_(IV) with the α-bromoamido intermediates 9_(IV) in the presence of base yields compounds of formula (IV).

The present disclosure provides compounds of formula (V):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, or —OMe;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In compounds of formula (V), R₁ is H or one or more substituents each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy. For example and without limitation, R₁ may in some embodiments be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy, or methoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₁ is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (V) are provided in Table 5 below.

TABLE 5 Example Compounds of Formula (V) Compound R₁ R₈ Alk R₇ m n p q 2290 H —N(Alk)₂ Me n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 5-Cl 2299 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2302 H —NH₂ Me n/a n/a 2 n/a n/a 2303 H

Me n/a 5 2 n/a n/a 2304 H

Me Me n/a 2 2 2

Referring now to FIG. 5 , compounds consistent with formula (V) can be synthesized by, for example, acylating alkylaminoalkylphenols 8_(V) with bromoacetyl bromide to form α-bromoamido intermediates 9_(V). Intermediates 11_(V) can be formed by alkylating anilines 10_(V) with β-haloamines 12_(V) in the presence of base. Combining intermediates 11_(V) with α-bromoamido intermediates 9_(V) in the presence of base yields compounds of formula (V).

The present disclosure provides compounds of formula (VI):

wherein:

-   -   R₁ is H, Cl, F, —CF₃, —OCF₃, —OMe, or methyl;     -   R₈ is selected from the group consisting of:         -   —NH₂, —N(H)Alk, —N(Alk)₂,

-   -   R₇ is H or alkyl;     -   m is 3 to 6;     -   p is 1 to 4;     -   q is 1 to 4;     -   p+q is 3 to 6; and     -   each Alk is independently an aliphatic carbon group consisting         of 1 to 6 carbon atoms.

In compounds of formula (VI), R₁ is H or one or more substituents each independently selected from the group consisting of: chloro, fluoro, trifluoromethyl, trifluoromethoxy, methoxy, and methyl. For example and without limitation, R₁ may in some embodiments be a single substituent that is chloro, fluoro, trifluoromethyl, trifluoromethoxy, or methoxy that is located at the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₁ is two or more substituents each independently selected from chloro, fluoro, trifluoromethyl, trifluoromethoxy, and methoxy located at any combination of the ortho-positions, the meta-positions, and the para-position of the aryl ring.

R₈ is an n-amino substituent selected from —NH₂, —N(H)Alk, —N(Alk)₂,

When R₈ is —N(H)Alk or —N(Alk)₂, Alk is an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). Alk may be linear, branched, or cyclic. When Alk is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When R₈ is

R₇ is H or alkyl. When R₇ is alkyl, the alkyl group can be an aliphatic carbon group consisting of 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be linear, branched, or cyclic. When the alkyl group is cyclic, the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₇ is H. In other embodiments, R₇ is methyl. In other embodiments, R₇ is ethyl. In other embodiments, R₇ is propyl (e.g., n-propyl or isopropyl). In other embodiments, R₇ is butyl (e.g., 1-butyl, 2-butyl, or t-butyl). In other embodiments, R₇ is pentyl (e.g., 1-n-pentyl, 2-n-pentyl, 3-n-pentyl, 2-methylbut-4-yl, 2-methylbuty-3-yl, or 1-dimethylprop-1-yl). In other embodiments, R₇ is hexyl (e.g., 1-n-hexyl, 2-n-hexyl, 3-n-hexyl, 2-methylpent-5-yl, 2-methylpent-4-yl, 2-methylpent-3-yl, 3-methylpent-5-yl, 2-methylpent-1-yl, 2,3-dimethylbut-4-yl, 2,2-dimethylbut-4-yl, 3,3-dimethylbut-4-yl, 2,3,3-trimethylprop-3-yl, 1,1-dimethylbut-1-yl, or 1,2,2-trimethylbut-1-yl).

When R₈ is

m is 3 to 6. In some embodiments, m is 3, resulting in a 4-membered N-azetidinyl group. In other embodiments, m is 4, resulting in a 5-membered N-pyrrolidinyl group. In other embodiments, m is 5, resulting in a 6-membered N-piperidinyl group. In other embodiments, m is 6, resulting in a 7-membered N-azepanyl group.

When R₈ is

p is 1 to 4, q is 1 to 4, and p and q together total 3 to 6. For example and without limitation, p may be 1 while q is 2, 3, 4 or 5. Alternatively, p may be 2 while q is 1, 2, 3, or 4. In other embodiments, p is 3 while q is 1, 2, or 3.

Some example compounds of formula (VI) are provided in Table 6 below.

TABLE 6 Example Compounds of Formula (VI) Compound R₁ R₈ Alk R₇ m n p q 2290 H —N(Alk)₂ Me n/a n/a 2 n/a n/a 2291 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 2292 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2293 o-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2294 p-OMe —N(Alk)₂ Me n/a n/a 2 n/a n/a 2295 o-Me —N(Alk)₂ Me n/a n/a 2 n/a n/a 2296 m-OCF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2297 m-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a p-Cl 2298 2-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a 5-C 2299 m-Cl —N(Alk)₂ Me n/a n/a 2 n/a n/a p-F 2300 2-F —N(Alk)₂ Me n/a n/a 2 n/a n/a 3-Cl 2301 o-CF₃ —N(Alk)₂ Me n/a n/a 2 n/a n/a 2302 H —NH₂ n/a n/a n/a 2 n/a n/a 2303 H

Me n/a 5 2 n/a n/a 2304 H

Me Me n/a 2 2 2

Referring now to FIG. 6 , compounds consistent with formula (VI) can be synthesized by, for example, acylating methylanilines 8_(VI) with bromoacetyl bromide to form intermediates 9_(VI). Intermediates 11_(VI) can be formed by alkylating anilines 10_(VI) with β-haloamines 12_(VI) in the presence of base. Combining intermediates 11_(VI) with intermediates 9_(VI) in the presence of base yields compounds of formula (VI).

The present disclosure provides compounds of formula (VII):

wherein:

-   -   R_(1a) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R_(1b) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1c) is H, Cl, F, or —OMe;     -   R_(1d) is H, Cl, F, —CF₃, or —OCF₃;     -   R_(1e) is H, Cl, F, —CF₃, —OMe, or methyl;     -   R₂ and R₃ are each independently H or alkyl or, taken together,         form a 4- to 8-membered heterocyclic ring with the adjacent         nitrogen atom;     -   R₄ is H or alkyl; and     -   R₅ is H or one or more electron donating groups.

In compounds of formula (VII), R_(1a) is H or an ortho-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, methoxy, or methyl. R_(1b) is H or a meta-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, or trifluoromethoxy. R_(1c) is H a para-substituent selected from the group consisting of: chloro, fluoro, or methoxy. R_(1d) is H or (e.g., when R_(1b) is not H) a meta-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, or trifluoromethoxy. R_(1e) is H or (e.g., when R_(1a) is not H) an ortho-substituent selected from the group consisting of: chloro, fluoro, trifluoromethyl, methoxy, or methyl. In some embodiments, R_(1a) is chloro, R_(1d) is chloro, and R_(1b), R_(1c), and R_(1e) are each H. In other embodiments, R_(1a) is fluoro, R_(1b) is chloro, and R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1a) is trifluoromethyl, and R_(1b), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1a) is methoxy, and R_(1b), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1a) is methyl, and R_(1b), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is chloro, R_(1c) is fluoro, and R_(1a), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is trifluoromethyl, R_(1e) is chloro, and R_(1a), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is trifluoromethoxyl, and R_(1a), R_(1c), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is chloro, R_(1e) is chloro, and R_(1a), R_(1d), and R_(1e) are each H. In other embodiments, R_(1b) is chloro, and R_(1a), R_(1e), R_(1d), and R_(1e) are each H. In other embodiments, R_(1e) is methoxyl, and R_(1a), Rib, Rid, and R_(1e) are each H.

Each R₂ and R₃ is independently H or alkyl. When R₂ and/or R₃ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

In some embodiments, R₂ and R₃ are covalently connected to form, with the adjacent nitrogen atom, a heterocyclic ring. The heterocyclic ring may include one to three nitrogen atoms and a total of four to eight atoms in the ring. The heterocyclic ring may be unsubstituted or substituted, for example with an alkyl or alkoxyl group. For example and without limitation, R₂ and R₃ may be covalently connected and include a total of five carbon atoms to form a piperidinyl ring including the nitrogen atom adjacent to R₂ and R₃. In other embodiments, R₂ and R₃ may, together, have a general formula —(CH₂)_(p)N(R₇)(CH₂)_(q)—, wherein p is 1 to 4, q is 1 to 4, p and q combined total 3 to 8, and R₇ is H or alkyl. When R₇ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. In some embodiments, R₂ and R₃ are both H. In other embodiments, R₂ and R₃ are both methyl. In still other embodiments, R₂ is H and R₃ is methyl.

R₄ is H or alkyl. When R₄ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is H or one or more electron donating groups. When R₅ is one or more electron donating groups, R₅ may be a single electron donating group in the ortho-, meta-, or para-position of the aryl ring. In other embodiments, R₅ may be two to five electron donating groups in any combination of ortho-, meta-, and para-positions of the aryl ring. Each electron donating group may be independently selected from alkyl and alkoxyl. When R₅ is alkyl, the alkyl group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three to six carbon atoms (i.e., C₃₋₆ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds. When R₅ is alkoxyl, the alkoxy group may be linear or branched, and may consist of one to six carbon atoms (i.e., C₁₋₆ alkoxy). The alkoxy group may be cyclic, in which case the alkoxy group may consist of three to six carbon atoms (i.e., C₃₋₆ alkoxy). The alkoxy group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VII) are provided in Table 7 below.

TABLE 7 Example Compounds of Formula (VII) Compound R_(1x) R₂ R₃ R₄ R₅ R₇ n p q 2290 a-e: H Me Me Me p-OMe n/a 2 n/a n/a 2291 a: H Me Me Me p-OMe n/a 2 n/a n/a b: Cl c-e: H 2292 a: H Me Me Me p-OMe n/a 2 n/a n/a b: Cl c: Cl d-e: H 2293 a: OMe Me Me Me p-OMe n/a 2 n/a n/a b-e: H 2294 a-b: H Me Me Me p-OMe n/a 2 n/a n/a c: OMe d-e: H 2295 a: Me Me Me Me p-OMe n/a 2 n/a n/a b-e: H 2296 a: H Me Me Me p-OMe n/a 2 n/a n/a b: OCF₃ c-e: H 2297 a: H Me Me Me p-OMe n/a 2 n/a n/a b: CF₃ c: Cl d-e: H 2298 a: Cl Me Me Me p-OMe n/a 2 n/a n/a b-c: H d: Cl e: H 2299 a: H Me Me Me p-OMe n/a 2 n/a n/a b: Cl c: F d-e: H 2300 a: F Me Me Me p-OMe n/a 2 n/a n/a b: Cl c-e: H 2301 a: CF₃ Me Me Me p-OMe n/a 2 n/a n/a b-e: H 2302 a-e: H H H Me p-OMe n/a 2 n/a n/a 2303 a-e: H —(CH₂)₅— Me p-OMe n/a 2 n/a n/a 2304 a-e: H —(CH₂)_(p)N(R₇)(CH₂)_(q)— Me p-OMe Me 2 2 2

Referring now to FIG. 7 , compounds consistent with formula (VII) can be synthesized by, for example, acylating anilines 8_(VII) with bromoacetyl bromide to form intermediates 9_(VII). Intermediates 11_(VII) can be formed by alkylating anilines 10_(VII) with β-haloamines 12_(VII) in the presence of base. Combining intermediates 11_(VII) with intermediates 9_(VII) in the presence of base yields compounds of formula (VII).

In other embodiments, the present disclosure provides a compound of formula (VIIIa):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIa), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIa) are provided in Table 8a below.

TABLE 8a Example Compounds of Formula (VIIIa) Compound R₂ R₃ R₄ R₅ 2290 Me Me Me —OMe 2305 Me Me Me —OEt 2306 Me Me Me —O-nPr 2307 Me Me Me —O-iPr 2308 Me Me Me —O-nBu 2309 Me Me Me —O-iBu 2310 Me Me Me —O-tBu 2311 Me Me Et —OMe 2312 Me Me nPr —OMe 2313 Me Me iPr —OMe 2314 Me Me nBu —OMe 2315 Me Me iBu —OMe 2316 Me Me tBu —OMe 2302 H H Me —OMe 2318 H H Me —OEt 2319 H H Me —O-nPr 2320 H H Me —O-iPr 2321 H H Me —O-nBu 2322 H H Me —O-iBu 2323 H H Me —O-tBu 2324 H H Et —OMe 2325 H H nPr —OMe 2326 H H iPr —OMe 2327 H H nBu —OMe 2328 H H iBu —OMe 2329 H H tBu —OMe 2330 H Me Me —OMe 2331 H Me Me —OEt 2332 H Me Me —O-nPr 2333 H Me Me —O-iPr 2334 H Me Me —O-nBu 2335 H Me Me —O-iBu 2336 H Me Me —O-tBu 2337 H Me Et —OMe 2338 H Me nPr —OMe 2339 H Me iPr —OMe 2340 H Me nBu —OMe 2341 H Me iBu —OMe 2342 H Me tBu —OMe

Referring now to FIG. 8 , compounds consistent with formula (VIIIa) can be synthesized by, for example, acylating para-substituted anilines 8a with bromoacetyl bromide to form intermediates 9a. Intermediates 11a can be formed by alkylating aniline 10a with β-haloamines 12a in the presence of base. Combining intermediates 11a with intermediates 9a in the presence of base yields compounds of formula (VIIIa).

In other embodiments, the present disclosure provides a compound of formula (VIIIb):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIb), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIb) are provided in Table 8b below.

TABLE 8b Example Compounds of Formula (VIIIb) Compound R₂ R₃ R₄ R₅ 2291 Me Me Me —OMe 2343 Me Me Me —OEt 2344 Me Me Me —O-nPr 2345 Me Me Me —O-iPr 2346 Me Me Me —O-nBu 2347 Me Me Me —O-iBu 2348 Me Me Me —O-tBu 2349 Me Me Et —OMe 2350 Me Me nPr —OMe 2351 Me Me iPr —OMe 2352 Me Me nBu —OMe 2353 Me Me iBu —OMe 2354 Me Me tBu —OMe 2355 H H Me —OMe 2356 H H Me —OEt 2357 H H Me —O-nPr 2358 H H Me —O-iPr 2359 H H Me —O-nBu 2360 H H Me —O-iBu 2361 H H Me —O-tBu 2362 H H Et —OMe 2363 H H nPr —OMe 2364 H H iPr —OMe 2365 H H nBu —OMe 2366 H H iBu —OMe 2367 H H tBu —OMe 2368 H Me Me —OMe 2369 H Me Me —OEt 2370 H Me Me —O-nPr 2371 H Me Me —O-iPr 2372 H Me Me —O-nBu 2373 H Me Me —O-iBu 2374 H Me Me —O-tBu 2375 H Me Et —OMe 2376 H Me nPr —OMe 2377 H Me iPr —OMe 2378 H Me nBu —OMe 2379 H Me iBu —OMe 2380 H Me tBu —OMe

Referring now to FIG. 9 , compounds consistent with formula (VIIIb) can be synthesized by, for example, acylating para-substituted anilines 8b with bromoacetyl bromide to form intermediates 9b. Intermediates 11b can be formed by alkylating m-chloroaniline 10b with β-haloamines 12b in the presence of base. Combining intermediates 11b with intermediates 9b in the presence of base yields compounds of formula (VIIIb).

In other embodiments, the present disclosure provides a compound of formula (VIIIc):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIc), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIc) are provided in Table 8c below.

TABLE 8c Example Compounds of Formula (VIIIc) Compound R₂ R₃ R₄ R₅ 2292 Me Me Me —OMe 2381 Me Me Me —OEt 2382 Me Me Me —O-nPr 2383 Me Me Me —O-iPr 2384 Me Me Me —O-nBu 2385 Me Me Me —O-iBu 2386 Me Me Me —O-tBu 2387 Me Me Et —OMe 2388 Me Me nPr —OMe 2389 Me Me iPr —OMe 2390 Me Me nBu —OMe 2391 Me Me iBu —OMe 2392 Me Me tBu —OMe 2393 H H Me —OMe 2394 H H Me —OEt 2395 H H Me —O-nPr 2396 H H Me —O-iPr 2397 H H Me —O-nBu 2398 H H Me —O-iBu 2399 H H Me —O-tBu 2400 H H Et —OMe 2401 H H nPr —OMe 2402 H H iPr —OMe 2403 H H nBu —OMe 2404 H H iBu —OMe 2405 H H tBu —OMe 2406 H Me Me —OMe 2407 H Me Me —OEt 2408 H Me Me —O-nPr 2409 H Me Me —O-iPr 2410 H Me Me —O-nBu 2411 H Me Me —O-iBu 2412 H Me Me —O-tBu 2413 H Me Et —OMe 2414 H Me nPr —OMe 2415 H Me iPr —OMe 2416 H Me nBu —OMe 2417 H Me iBu —OMe 2418 H Me tBu —OMe

Referring now to FIG. 10 , compounds consistent with formula (VIIIc) can be synthesized by, for example, acylating para-substituted anilines 8c with bromoacetyl bromide to form intermediates 9c. Intermediates 11c can be formed by alkylating m-chloroaniline 10c with β-haloamines 12c in the presence of base. Combining intermediates 11c with intermediates 9c in the presence of base yields compounds of formula (VIIIc).

In other embodiments, the present disclosure provides a compound of formula (VIIId):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIId), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIId) are provided in Table 8d below.

TABLE 8d Example Compounds of Formula (VIIId) Compound R₂ R₃ R₄ R₅ 2293 Me Me Me —OMe 2420 Me Me Me —OEt 2421 Me Me Me —O-nPr 2422 Me Me Me —O-iPr 2423 Me Me Me —O-nBu 2424 Me Me Me —O-iBu 2425 Me Me Me —O-tBu 2426 Me Me Et —OMe 2427 Me Me nPr —OMe 2428 Me Me iPr —OMe 2429 Me Me nBu —OMe 2430 Me Me iBu —OMe 2431 Me Me tBu —OMe 2432 H H Me —OMe 2433 H H Me —OEt 2434 H H Me —O-nPr 2435 H H Me —O-iPr 2436 H H Me —O-nBu 2437 H H Me —O-iBu 2438 H H Me —O-tBu 2439 H H Et —OMe 2440 H H nPr —OMe 2441 H H iPr —OMe 2442 H H nBu —OMe 2443 H H iBu —OMe 2444 H H tBu —OMe 2445 H Me Me —OMe 2446 H Me Me —OEt 2447 H Me Me —O-nPr 2448 H Me Me —O-iPr 2449 H Me Me —O-nBu 2450 H Me Me —O-iBu 2451 H Me Me —O-tBu 2452 H Me Et —OMe 2453 H Me nPr —OMe 2454 H Me iPr —OMe 2455 H Me nBu —OMe 2456 H Me iBu —OMe 2457 H Me tBu —OMe

Referring now to FIG. 11 , compounds consistent with formula (VIIId) can be synthesized by, for example, acylating para-substituted anilines 8d with bromoacetyl bromide to form intermediates 9d. Intermediates 11d can be formed by alkylating o-methoxyaniline 10d with β-haloamines 12d in the presence of base. Combining intermediates 11d with intermediates 9d in the presence of base yields compounds of formula (VIIId).

In other embodiments, the present disclosure provides a compound of formula (VIIIe):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIe), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIe) are provided in Table 8e below.

TABLE 8e Example Compounds of Formula (VIIIe) Compound R₂ R₃ R₄ R₅ 2294 Me Me Me —OMe 2459 Me Me Me —OEt 2460 Me Me Me —O-nPr 2461 Me Me Me —O-iPr 2462 Me Me Me —O-nBu 2463 Me Me Me —O-iBu 2464 Me Me Me —O-tBu 2465 Me Me Et —OMe 2466 Me Me nPr —OMe 2467 Me Me iPr —OMe 2468 Me Me nBu —OMe 2469 Me Me iBu —OMe 2470 Me Me tBu —OMe 2471 H H Me —OMe 2472 H H Me —OEt 2473 H H Me —O-nPr 2474 H H Me —O-iPr 2475 H H Me —O-nBu 2476 H H Me —O-iBu 2477 H H Me —O-tBu 2478 H H Et —OMe 2479 H H nPr —OMe 2480 H H iPr —OMe 2481 H H nBu —OMe 2482 H H iBu —OMe 2483 H H tBu —OMe 2484 H Me Me —OMe 2485 H Me Me —OEt 2486 H Me Me —O-nPr 2487 H Me Me —O-iPr 2488 H Me Me —O-nBu 2489 H Me Me —O-iBu 2490 H Me Me —O-tBu 2491 H Me Et —OMe 2492 H Me nPr —OMe 2493 H Me iPr —OMe 2494 H Me nBu —OMe 2495 H Me iBu —OMe 2496 H Me tBu —OMe

Referring now to FIG. 12 , compounds consistent with formula (VIIIe) can be synthesized by, for example, acylating para-substituted anilines 8e with bromoacetyl bromide to form intermediates 9e. Intermediates 11e can be formed by alkylating p-methoxyaniline 10e with β-haloamines 12e in the presence of base. Combining intermediates 11e with intermediates 9e in the presence of base yields compounds of formula (VIIIe).

In other embodiments, the present disclosure provides a compound of formula (VIIIf):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIf), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIf) are provided in Table 8f below.

TABLE 8f Example Compounds of Formula (VIIIf) Compound R₂ R₃ R₄ R₅ 2295 Me Me Me —OMe 2498 Me Me Me —OEt 2499 Me Me Me —O-nPr 2500 Me Me Me —O-iPr 2501 Me Me Me —O-nBu 2502 Me Me Me —O-iBu 2503 Me Me Me —O-tBu 2504 Me Me Et —OMe 2505 Me Me nPr —OMe 2506 Me Me iPr —OMe 2507 Me Me nBu —OMe 2508 Me Me iBu —OMe 2509 Me Me tBu —OMe 2510 H H Me —OMe 2511 H H Me —OEt 2512 H H Me —O-nPr 2513 H H Me —O-iPr 2514 H H Me —O-nBu 2515 H H Me —O-iBu 2516 H H Me —O-tBu 2517 H H Et —OMe 2518 H H nPr —OMe 2519 H H iPr —OMe 2520 H H nBu —OMe 2521 H H iBu —OMe 2522 H H tBu —OMe 2523 H Me Me —OMe 2524 H Me Me —OEt 2525 H Me Me —O-nPr 2526 H Me Me —O-iPr 2527 H Me Me —O-nBu 2528 H Me Me —O-iBu 2529 H Me Me —O-tBu 2530 H Me Et —OMe 2531 H Me nPr —OMe 2532 H Me iPr —OMe 2533 H Me nBu —OMe 2534 H Me iBu —OMe 2535 H Me tBu —OMe

Referring now to FIG. 13 , compounds consistent with formula (VIIIf) can be synthesized by, for example, acylating para-substituted anilines 8f with bromoacetyl bromide to form intermediates 9f. Intermediates 11f can be formed by alkylating p-methoxyaniline 10f with β-haloamines 12f in the presence of base. Combining intermediates 11f with intermediates 9f in the presence of base yields compounds of formula (VIIIf).

In other embodiments, the present disclosure provides a compound of formula (VIIIg):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIg), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIg) are provided in Table 8g below.

TABLE 8g Example Compounds of Formula (VIIIg) Compound R₂ R₃ R₄ R₅ 2296 Me Me Me —OMe 2537 Me Me Me —OEt 2538 Me Me Me —O-nPr 2539 Me Me Me —O-iPr 2540 Me Me Me —O-nBu 2541 Me Me Me —O-iBu 2542 Me Me Me —O-tBu 2543 Me Me Et —OMe 2544 Me Me nPr —OMe 2545 Me Me iPr —OMe 2546 Me Me nBu —OMe 2547 Me Me iBu —OMe 2548 Me Me tBu —OMe 2549 H H Me —OMe 2550 H H Me —OEt 2551 H H Me —O-nPr 2552 H H Me —O-iPr 2553 H H Me —O-nBu 2554 H H Me —O-iBu 2555 H H Me —O-tBu 2556 H H Et —OMe 2557 H H nPr —OMe 2558 H H iPr —OMe 2559 H H nBu —OMe 2560 H H iBu —OMe 2561 H H tBu —OMe 2562 H Me Me —OMe 2563 H Me Me —OEt 2564 H Me Me —O-nPr 2565 H Me Me —O-iPr 2566 H Me Me —O-nBu 2567 H Me Me —O-iBu 2568 H Me Me —O-tBu 2569 H Me Et —OMe 2570 H Me nPr —OMe 2571 H Me iPr —OMe 2572 H Me nBu —OMe 2573 H Me iBu —OMe 2574 H Me tBu —OMe

Referring now to FIG. 14 , compounds consistent with formula (VIIIg) can be synthesized by, for example, acylating para-substituted anilines 8g with bromoacetyl bromide to form intermediates 9g. Intermediates 11g can be formed by alkylating m-trifluoromethoxyaniline 10g with p-haloamines 12g in the presence of base. Combining intermediates 11g with intermediates 9g in the presence of base yields compounds of formula (VIIIg).

In other embodiments, the present disclosure provides a compound of formula (VIIIh):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIh), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIh) are provided in Table 8h below.

TABLE 8h Example Compounds of Formula (VIIIh) Compound R₂ R₃ R₄ R₅ 2297 Me Me Me —OMe 2576 Me Me Me —OEt 2577 Me Me Me —O—nPr 2578 Me Me Me —O—iPr 2579 Me Me Me —O—nBu 2580 Me Me Me —O—iBu 2581 Me Me Me —O—tBu 2582 Me Me Et —OMe 2583 Me Me nPr —OMe 2584 Me Me iPr —OMe 2585 Me Me nBu —OMe 2586 Me Me iBu —OMe 2587 Me Me tBu —OMe 2588 H H Me —OMe 2589 H H Me —OEt 2590 H H Me —O—nPr 2591 H H Me —O—iPr 2592 H H Me —O—nBu 2593 H H Me —O—iBu 2594 H H Me —O—tBu 2595 H H Et —OMe 2596 H H nPr —OMe 2597 H H iPr —OMe 2598 H H nBu —OMe 2599 H H iBu —OMe 2600 H H tBu —OMe 2601 H Me Me —OMe 2602 H Me Me —OEt 2603 H Me Me —O—nPr 2604 H Me Me —O—iPr 2605 H Me Me —O—nBu 2606 H Me Me —O—iBu 2607 H Me Me —O—tBu 2608 H Me Et —OMe 2609 H Me nPr —OMe 2610 H Me iPr —OMe 2611 H Me nBu —OMe 2612 H Me iBu —OMe 2613 H Me tBu —OMe

Referring now to FIG. 15 , compounds consistent with formula (VIIIh) can be synthesized by, for example, acylating para-substituted anilines 8h with bromoacetyl bromide to form intermediates 9h. Intermediates 11h can be formed by alkylating p-chloro-m-trifluoromethylaniline 10h with p-haloamines 12h in the presence of base. Combining intermediates 11h with intermediates 9h in the presence of base yields compounds of formula (VIIIh).

In other embodiments, the present disclosure provides a compound of formula (VIIIi):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIi), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIi) are provided in Table 8i below.

TABLE 8i Example Compounds of Formula (VIIIi) Compound R₂ R₃ R₄ R₅ 2298 Me Me Me —OMe 2615 Me Me Me —OEt 2616 Me Me Me —O—nPr 2617 Me Me Me —O—iPr 2618 Me Me Me —O—nBu 2619 Me Me Me —O—iBu 2620 Me Me Me —O—tBu 2621 Me Me Et —OMe 2622 Me Me nPr —OMe 2623 Me Me iPr —OMe 2624 Me Me nBu —OMe 2625 Me Me iBu —OMe 2626 Me Me tBu —OMe 2627 H H Me —OMe 2628 H H Me —OEt 2629 H H Me —O—nPr 2630 H H Me —O—iPr 2631 H H Me —O—nBu 2632 H H Me —O—iBu 2633 H H Me —O—tBu 2634 H H Et —OMe 2635 H H nPr —OMe 2636 H H iPr —OMe 2637 H H nBu —OMe 2638 H H iBu —OMe 2639 H H tBu —OMe 2640 H Me Me —OMe 2641 H Me Me —OEt 2642 H Me Me —O—nPr 2643 H Me Me —O—iPr 2644 H Me Me —O—nBu 2645 H Me Me —O—iBu 2646 H Me Me —O—tBu 2647 H Me Et —OMe 2648 H Me nPr —OMe 2649 H Me iPr —OMe 2650 H Me nBu —OMe 2651 H Me iBu —OMe 2652 H Me tBu —OMe

Referring now to FIG. 16 , compounds consistent with formula (VIIIi) can be synthesized by, for example, acylating para-substituted anilines 8i with bromoacetyl bromide to form intermediates 9i. Intermediates 11i can be formed by alkylating 2,5-dichloroaniline 10i with β-haloamines 12i in the presence of base. Combining intermediates 11i with intermediates 9i in the presence of base yields compounds of formula (VIIIi).

In other embodiments, the present disclosure provides a compound of formula (VIIIj):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIj), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIj) are provided in Table 8j below.

TABLE 8j Example Compounds of Formula (VIIIj) Compound R₂ R₃ R₄ R₅ 2299 Me Me Me —OMe 2654 Me Me Me —OEt 2655 Me Me Me —O—nPr 2656 Me Me Me —O—iPr 2657 Me Me Me —O—nBu 2658 Me Me Me —O—iBu 2659 Me Me Me —O—tBu 2660 Me Me Et —OMe 2661 Me Me nPr —OMe 2662 Me Me iPr —OMe 2663 Me Me nBu —OMe 2664 Me Me iBu —OMe 2665 Me Me tBu —OMe 2666 H H Me —OMe 2667 H H Me —OEt 2668 H H Me —O—nPr 2669 H H Me —O—iPr 2670 H H Me —O—nBu 2671 H H Me —O—iBu 2672 H H Me —O—tBu 2673 H H Et —OMe 2674 H H nPr —OMe 2675 H H iPr —OMe 2676 H H nBu —OMe 2677 H H iBu —OMe 2678 H H tBu —OMe 2679 H Me Me —OMe 2680 H Me Me —OEt 2681 H Me Me —O—nPr 2682 H Me Me —O—iPr 2683 H Me Me —O—nBu 2684 H Me Me —O—iBu 2685 H Me Me —O—tBu 2686 H Me Et —OMe 2687 H Me nPr —OMe 2688 H Me iPr —OMe 2689 H Me nBu —OMe 2690 H Me iBu —OMe 2691 H Me tBu —OMe

Referring now to FIG. 17 , compounds consistent with formula (VIIIj) can be synthesized by, for example, acylating para-substituted anilines 8j with bromoacetyl bromide to form intermediates 9j. Intermediates 11j can be formed by alkylating 3-chloro-4-fluoroaniline 10j with β-haloamines 12j in the presence of base. Combining intermediates 11j with intermediates 9j in the presence of base yields compounds of formula (VIIIj).

In other embodiments, the present disclosure provides a compound of formula (VIIIk):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIk), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIk) are provided in Table 8k below.

TABLE 8k Example Compounds of Formula (VIIIk) Compound R₂ R₃ R₄ R₅ 2300 Me Me Me —OMe 2693 Me Me Me —OEt 2694 Me Me Me —O—nPr 2695 Me Me Me —O—iPr 2696 Me Me Me —O—nBu 2697 Me Me Me —O—iBu 2698 Me Me Me —O—tBu 2699 Me Me Et —OMe 2700 Me Me nPr —OMe 2701 Me Me iPr —OMe 2702 Me Me nBu —OMe 2703 Me Me iBu —OMe 2704 Me Me tBu —OMe 2705 H H Me —OMe 2706 H H Me —OEt 2707 H H Me —O—nPr 2708 H H Me —O—iPr 2709 H H Me —O—nBu 2710 H H Me —O—iBu 2711 H H Me —O—tBu 2712 H H Et —OMe 2713 H H nPr —OMe 2714 H H iPr —OMe 2715 H H nBu —OMe 2716 H H iBu —OMe 2717 H H tBu —OMe 2718 H Me Me —OMe 2719 H Me Me —OEt 2720 H Me Me —O—nPr 2721 H Me Me —O—iPr 2722 H Me Me —O—nBu 2723 H Me Me —O—iBu 2724 H Me Me —O—tBu 2725 H Me Et —OMe 2726 H Me nPr —OMe 2727 H Me iPr —OMe 2728 H Me nBu —OMe 2729 H Me iBu —OMe 2730 H Me tBu —OMe

Referring now to FIG. 18 , compounds consistent with formula (VIIIk) can be synthesized by, for example, acylating para-substituted anilines 8k with bromoacetyl bromide to form intermediates 9k. Intermediates 11 k can be formed by alkylating 2-fluoro-3-chloroaniline 10k with β-haloamines 12k in the presence of base. Combining intermediates 11 k with intermediates 9k in the presence of base yields compounds of formula (VIIIk).

In other embodiments, the present disclosure provides a compound of formula (VIIIm):

wherein:

-   -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIm), each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

Some example compounds of formula (VIIIm) are provided in Table 8m below.

TABLE 8m Example Compounds of Formula (VIIIm) Compound R₂ R₃ R₄ R₅ 2301 Me Me Me —OMe 2732 Me Me Me —OEt 2733 Me Me Me —O—nPr 2734 Me Me Me —O—iPr 2735 Me Me Me —O—nBu 2736 Me Me Me —O—iBu 2737 Me Me Me —O—tBu 2738 Me Me Et —OMe 2739 Me Me nPr —OMe 2740 Me Me iPr —OMe 2741 Me Me nBu —OMe 2742 Me Me iBu —OMe 2743 Me Me tBu —OMe 2744 H H Me —OMe 2745 H H Me —OEt 2746 H H Me —O—nPr 2747 H H Me —O—iPr 2748 H H Me —O—nBu 2749 H H Me —O—iBu 2750 H H Me —O—tBu 2751 H H Et —OMe 2752 H H nPr —OMe 2753 H H iPr —OMe 2754 H H nBu —OMe 2755 H H iBu —OMe 2756 H H tBu —OMe 2757 H Me Me —OMe 2758 H Me Me —OEt 2759 H Me Me —O—nPr 2760 H Me Me —O—iPr 2761 H Me Me —O—nBu 2762 H Me Me —O—iBu 2763 H Me Me —O—tBu 2764 H Me Et —OMe 2765 H Me nPr —OMe 2766 H Me iPr —OMe 2767 H Me nBu —OMe 2768 H Me iBu —OMe 2769 H Me tBu —OMe

Referring now to FIG. 19 , compounds consistent with formula (VIIIm) can be synthesized by, for example, acylating para-substituted anilines 8m with bromoacetyl bromide to form intermediates 9m. Intermediates 11m can be formed by alkylating o-trifluoromethylaniline 10m with p-haloamines 12m in the presence of base. Combining intermediates 11m with intermediates 9m in the presence of base yields compounds of formula (VIIIm).

In other embodiments, the present disclosure provides a compound of formula (VIIIn):

wherein:

-   -   A=C or N;     -   R₂=H or Me;     -   R₃=H or Me;     -   R₄=Alkyl;     -   R₅=O-Alkyl;     -   when A=C, then R₁₀=R₁₁=H; or when A=N, then R₁₀=Alkyl and         R₁₁=null; and     -   Alkyl=aliphatic C₁-C₄ alkyl.

In compounds of formula (VIIIn), A is selected from the group consisting of carbon and nitrogen.

Each R₂ and R₃ is independently H or methyl; in some embodiments both R₂ and R₃ are H. In other embodiments, both R₂ and R₃ are methyl. In some embodiments, one of R₂ and R₃ is H while the other is methyl.

R₄ is Alkyl; may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

R₅ is an O-Alkyl (i.e., alkoxy) at the para position. The alkyl group may be linear or branched, and may consist of one to four carbon atoms (i.e., C₁₋₄ alkyl). The alkyl group may be cyclic, in which case the alkyl group may consist of three or four carbon atoms (i.e., C₃₋₄ cycloalkyl). The alkyl group may be saturated or unsaturated with one or more carbon-carbon double bonds and/or carbon-carbon triple bonds.

When A is carbon, then R₁₀ and R₁₁ are both hydrogen. When A is nitrogen, then R₁₀ is Alkyl and R₁₁ is no atom (null).

Some example compounds of formula (VIIIn) are provided in Table 8n below.

TABLE 8n Example Compounds of Formula (VIIIn) Compound R₄ R₅ A R₁₀ R₁₁ 2303 Me —OMe C H H 2771 Me —OEt C H H 2772 Me —O—nPr C H H 2773 Me —O—iPr C H H 2774 Me —O—nBu C H H 2775 Me —O—iBu C H H 2776 Me —O—tBu C H H 2777 Et —OMe C H H 2778 nPr —OMe C H H 2779 iPr —OMe C H H 2780 nBu —OMe C H H 2781 iBu —OMe C H H 2782 tBu —OMe C H H 2783 Me —OMe C H H 2784 Me —OEt C H H 2785 Me —O—nPr C H H 2786 Me —O—iPr C H H 2787 Me —O—nBu C H H 2788 Me —O—iBu C H H 2789 Me —O—tBu C H H 2790 Et —OMe C H H 2791 nPr —OMe C H H 2792 iPr —OMe C H H 2793 nBu —OMe C H H 2794 iBu —OMe C H H 2795 tBu —OMe C H H 2796 Me —OMe C H H 2797 Me —OEt C H H 2798 Me —O—nPr C H H 2799 Me —O—iPr C H H 2800 Me —O—nBu C H H 2801 Me —O—iBu C H H 2802 Me —O—tBu C H H 2803 Et —OMe C H H 2804 nPr —OMe C H H 2805 iPr —OMe C H H 2806 nBu —OMe C H H 2807 iBu —OMe C H H 2808 tBu —OMe C H H 2304 Me —OMe N Me null 2810 Me —OEt N Me null 2811 Me —O—nPr N Me null 2812 Me —O—iPr N Me null 2813 Me —O—nBu N Me null 2814 Me —O—iBu N Me null 2815 Me —O—tBu N Me null 2816 Et —OMe N Me null 2817 nPr —OMe N Me null 2818 iPr —OMe N Me null 2819 nBu —OMe N Me null 2820 iBu —OMe N Me null 2821 tBu —OMe N Me null 2822 Me —OMe N Me null 2823 Me —OEt N Me null 2824 Me —O—nPr N Me null 2825 Me —O—iPr N Me null 2826 Me —O—nBu N Me null 2827 Me —O—iBu N Me null 2828 Me —O—tBu N Me null 2829 Et —OMe N Me null 2830 nPr —OMe N Me null 2831 iPr —OMe N Me null 2832 nBu —OMe N Me null 2833 iBu —OMe N Me null 2834 tBu —OMe N Me null 2835 Me —OMe N Me null 2836 Me —OEt N Me null 2837 Me —O—nPr N Me null 2838 Me —O—iPr N Me null 2839 Me —O—nBu N Me null 2840 Me —O—iBu N Me null 2841 Me —O—tBu N Me null 2842 Et —OMe N Me null 2843 nPr —OMe N Me null 2844 iPr —OMe N Me null 2845 nBu —OMe N Me null 2846 iBu —OMe N Me null 2847 tBu —OMe N Me null 2848 Me —OMe N Et null 2849 Me —OEt N Et null 2850 Me —O—nPr N Et null 2851 Me —O—iPr N Et null 2852 Me —O—nBu N Et null 2853 Me —O—iBu N Et null 2854 Me —O—tBu N Et null 2855 Et —OMe N Et null 2856 nPr —OMe N Et null 2857 iPr —OMe N Et null 2858 nBu —OMe N Et null 2859 iBu —OMe N Et null 2860 tBu —OMe N Et null 2861 Me —OMe N Et null 2862 Me —OEt N Et null 2863 Me —O—nPr N Et null 2864 Me —O—iPr N Et null 2865 Me —O—nBu N Et null 2866 Me —O—iBu N Et null 2867 Me —O—tBu N Et null 2868 Et —OMe N Et null 2869 nPr —OMe N Et null 2870 iPr —OMe N Et null 2871 nBu —OMe N Et null 2872 iBu —OMe N Et null 2873 tBu —OMe N Et null 2874 Me —OMe N Et null 2875 Me —OEt N Et null 2876 Me —O—nPr N Et null 2877 Me —O—iPr N Et null 2878 Me —O—nBu N Et null 2879 Me —O—iBu N Et null 2880 Me —O—tBu N Et null 2881 Et —OMe N Et null 2882 nPr —OMe N Et null 2883 iPr —OMe N Et null 2884 nBu —OMe N Et null 2885 iBu —OMe N Et null 2886 tBu —OMe N Et null 2887 Me —OMe N nPr null 2888 Me —OEt N nPr null 2889 Me —O—nPr N nPr null 2890 Me —O—iPr N nPr null 2891 Me —O—nBu N nPr null 2892 Me —O—iBu N nPr null 2893 Me —O—tBu N nPr null 2894 Et —OMe N nPr null 2895 nPr —OMe N nPr null 2896 iPr —OMe N nPr null 2897 nBu —OMe N nPr null 2898 iBu —OMe N nPr null 2899 tBu —OMe N nPr null 2900 Me —OMe N nPr null 2901 Me —OEt N nPr null 2902 Me —O—nPr N nPr null 2903 Me —O—iPr N nPr null 2904 Me —O—nBu N nPr null 2905 Me —O—iBu N nPr null 2906 Me —O—tBu N nPr null 2907 Et —OMe N nPr null 2908 nPr —OMe N nPr null 2909 iPr —OMe N nPr null 2910 nBu —OMe N nPr null 2911 iBu —OMe N nPr null 2912 tBu —OMe N nPr null 2913 Me —OMe N nPr null 2914 Me —OEt N nPr null 2915 Me —O—nPr N nPr null 2916 Me —O—iPr N nPr null 2917 Me —O—nBu N nPr null 2918 Me —O—iBu N nPr null 2919 Me —O—tBu N nPr null 2920 Et —OMe N nPr null 2921 nPr —OMe N nPr null 2922 iPr —OMe N nPr null 2923 nBu —OMe N nPr null 2924 iBu —OMe N nPr null 2925 tBu —OMe N nPr null 2926 Me —OMe N iPr null 2927 Me —OEt N iPr null 2928 Me —O—nPr N iPr null 2929 Me —O—iPr N iPr null 2930 Me —O—nBu N iPr null 2931 Me —O—iBu N iPr null 2932 Me —O—tBu N iPr null 2933 Et —OMe N iPr null 2934 nPr —OMe N iPr null 2935 iPr —OMe N iPr null 2936 nBu —OMe N iPr null 2937 iBu —OMe N iPr null 2938 tBu —OMe N iPr null 2939 Me —OMe N iPr null 2940 Me —OEt N iPr null 2941 Me —O—nPr N iPr null 2942 Me —O—iPr N iPr null 2943 Me —O—nBu N iPr null 2944 Me —O—iBu N iPr null 2945 Me —O—tBu N iPr null 2946 Et —OMe N iPr null 2947 nPr —OMe N iPr null 2948 iPr —OMe N iPr null 2949 nBu —OMe N iPr null 2950 iBu —OMe N iPr null 2951 tBu —OMe N iPr null 2952 Me —OMe N iPr null 2953 Me —OEt N iPr null 2954 Me —O—nPr N iPr null 2955 Me —O—iPr N iPr null 2956 Me —O—nBu N iPr null 2957 Me —O—iBu N iPr null 2958 Me —O—tBu N iPr null 2959 Et —OMe N iPr null 2960 nPr —OMe N iPr null 2961 iPr —OMe N iPr null 2962 nBu —OMe N iPr null 2963 iBu —OMe N iPr null 2964 tBu —OMe N iPr null 2965 Me —OMe N nBu null 2966 Me —OEt N nBu null 2967 Me —O—nPr N nBu null 2968 Me —O—iPr N nBu null 2969 Me —O—nBu N nBu null 2970 Me —O—iBu N nBu null 2971 Me —O—tBu N nBu null 2972 Et —OMe N nBu null 2973 nPr —OMe N nBu null 2974 iPr —OMe N nBu null 2975 nBu —OMe N nBu null 2976 iBu —OMe N nBu null 2977 tBu —OMe N nBu null 2978 Me —OMe N nBu null 2979 Me —OEt N nBu null 2980 Me —O—nPr N nBu null 2981 Me —O—iPr N nBu null 2982 Me —O—nBu N nBu null 2983 Me —O—iBu N nBu null 2984 Me —O—tBu N nBu null 2985 Et —OMe N nBu null 2986 nPr —OMe N nBu null 2987 iPr —OMe N nBu null 2988 nBu —OMe N nBu null 2989 iBu —OMe N nBu null 2990 tBu —OMe N nBu null 2991 Me —OMe N nBu null 2992 Me —OEt N nBu null 2993 Me —O—nPr N nBu null 2994 Me —O—iPr N nBu null 2995 Me —O—nBu N nBu null 2996 Me —O—iBu N nBu null 2997 Me —O—tBu N nBu null 2998 Et —OMe N nBu null 2999 nPr —OMe N nBu null 3000 iPr —OMe N nBu null 3001 nBu —OMe N nBu null 3002 iBu —OMe N nBu null 3003 tBu —OMe N nBu null 3004 Me —OMe N iBu null 3005 Me —OEt N iBu null 3006 Me —O—nPr N iBu null 3007 Me —O—iPr N iBu null 3008 Me —O—nBu N iBu null 3009 Me —O—iBu N iBu null 3010 Me —O—tBu N iBu null 3011 Et —OMe N iBu null 3012 nPr —OMe N iBu null 3013 iPr —OMe N iBu null 3014 nBu —OMe N iBu null 3015 iBu —OMe N iBu null 3016 tBu —OMe N iBu null 3017 Me —OMe N iBu null 3018 Me —OEt N iBu null 3019 Me —O—nPr N iBu null 3020 Me —O—iPr N iBu null 3021 Me —O—nBu N iBu null 3022 Me —O—iBu N iBu null 3023 Me —O—tBu N iBu null 3024 Et —OMe N iBu null 3025 nPr —OMe N iBu null 3026 iPr —OMe N iBu null 3027 nBu —OMe N iBu null 3028 iBu —OMe N iBu null 3029 tBu —OMe N iBu null 3030 Me —OMe N iBu null 3031 Me —OEt N iBu null 3032 Me —O—nPr N iBu null 3033 Me —O—iPr N iBu null 3034 Me —O—nBu N iBu null 3035 Me —O—iBu N iBu null 3036 Me —O—tBu N iBu null 3037 Et —OMe N iBu null 3038 nPr —OME N iBu null 3039 iPr —OMe N iBu null 3040 nBu —OMe N iBu null 3041 iBu —OMe N iBu null 3042 tBu —OMe N iBu null 3043 Me —OMe N tBu null 3044 Me —OEt N tBu null 3045 Me —O—nPr N tBu null 3046 Me —O—iPr N tBu null 3047 Me —O—nBu N tBu null 3048 Me —O—iBu N tBu null 3049 Me —O—tBu N tBu null 3050 Et —OMe N tBu null 3051 nPr —OMe N tBu null 3052 iPr —OMe N tBu null 3053 nBu —OMe N tBu null 3054 iBu —OMe N tBu null 3055 tBu —OMe N tBu null 3056 Me —OMe N tBu null 3057 Me —OEt N tBu null 3058 Me —O—nPr N tBu null 3059 Me —O—iPr N tBu null 3060 Me —O—nBu N tBu null 3061 Me —O—iBu N tBu null 3062 Me —O—tBu N tBu null 3063 Et —OMe N tBu null 3064 nPr —OMe N tBu null 3065 iPr —OMe N tBu null 3066 nBu —OMe N tBu null 3067 iBu —OMe N tBu null 3068 tBu —OMe N tBu null 3069 Me —OMe N tBu null 3070 Me —OEt N tBu null 3071 Me —O—nPr N tBu null 3072 Me —O—iPr N tBu null 3073 Me —O—nBu N tBu null 3074 Me —O—iBu N tBu null 3075 Me —O—tBu N tBu null 3076 Et —OMe N tBu null 3077 nPr —OMe N tBu null 3078 iPr —OMe N tBu null 3079 nBu —OMe N tBu null 3080 iBu —OMe N tBu null 3081 tBu —OMe N tBu null

Referring now to FIG. 20 , compounds consistent with formula (VIIIn) can be synthesized by, for example, acylating para-substituted anilines 8n with bromoacetyl bromide to form intermediates 9n. Intermediates 11n can be formed by alkylating aniline 10n with β-halogenated cycloamines 12 n in the presence of base. Combining intermediates 11n with intermediates 9n in the presence of base yields compounds of formula (VIIIn).

In other embodiments, the present disclosure provides a compound of formula (IX):

wherein R₁ is selected from the group consisting of: H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl; m-trifluoromethoxy; m-trifluoromethyl-p-chloro; 2,5-dichloro; 3-chloro-4-fluoro; 2-fluoro-3-chloro; and o-trifluoromethyl.

Some example compounds of formula (IX) are provided in Table 9 below.

TABLE 9 Example Compounds of Formula (IX) Compound R₁ 2290 H 2291 m-chloro 2292 3,4-dichloro 2293 o-methoxy 2294 p-methoxy 2295 o-methyl 2296 m-trifluoromethoxy 2297 m-trifluoromethyl-p-chloro 2298 2,5-dichloro 2299 3-chloro-4-fluoro 2300 2-fluoro-3-chloro 2301 o-trifluoromethyl

Referring now to FIG. 21 , compounds consistent with formula (IX) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(IX) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(IX). Intermediates 11_(IX) can be formed by alkylating R₁-substituted anilines 10_(IX) with p-halo-N,N,-dimethylamines 12_(IX) in the presence of base. Combining intermediates 11_(IX) with intermediates 9_(IX) in the presence of base yields compounds of formula (IX).

In other embodiments, the present disclosure provides a compound of formula (X):

wherein R₁ is selected from the group consisting of: H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl; m-trifluoromethoxy; m-trifluoromethyl-p-chloro; 2,5-dichloro; 3-chloro-4-fluoro; 2-fluoro-3-chloro; and o-trifluoromethyl.

Some example compounds of formula (X) are provided in Table 10 below.

TABLE 10 Example Compounds of Formula (X) Compound R₁ 2302 H 3094 m-chloro 3095 3,4-dichloro 3096 o-methoxy 3097 p-methoxy 3098 o-methyl 3099 m-trifluoromethoxy 3100 m-trifluoromethyl-p-chloro 3102 2,5-dichloro 3103 3-chloro-4-fluoro 3104 2-fluoro-3-chloro 3105 o-trifluoromethyl

Referring now to FIG. 22 , compounds consistent with formula (X) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(X) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(X). Intermediates 11_(X) can be formed by alkylating R₁-substituted anilines 10_(X) with β-haloamines 12_(X) in the presence of base. Combining intermediates 11_(X) with intermediates 9_(X) in the presence of base yields compounds of formula (X).

In other embodiments, the present disclosure provides a compound of formula (XI):

wherein R₁ is selected from the group consisting of: H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl; m-trifluoromethoxy; m-trifluoromethyl-p-chloro; 2,5-dichloro; 3-chloro-4-fluoro; 2-fluoro-3-chloro; and o-trifluoromethyl.

Some example compounds of formula (XI) are provided in Table 11 below.

TABLE 11 Example Compounds of Formula (XI) Compound R₁ 2303 H 3106 m-chloro 3107 3,4-dichloro 3108 o-methoxy 3109 p-methoxy 3110 o-methyl 3111 m-trifluoromethoxy 3112 m-trifluoromethyl-p-chloro 3114 2,5-dichloro 3115 3-chloro-4-fluoro 3116 2-fluoro-3-chloro 3117 o-trifluoromethyl

Referring now to FIG. 23 , compounds consistent with formula (XI) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XI) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XI). Intermediates 11_(XI) can be formed by alkylating R₁-substituted anilines 10_(XI) with N-(β-haloethyl)piperdine 12_(XI) in the presence of base. Combining intermediates 11_(XI) with intermediates 9_(XI) in the presence of base yields compounds of formula (XI).

In other embodiments, the present disclosure provides a compound of formula (XII):

wherein R₁ is selected from the group consisting of: H, m-chloro; 3,4-dichloro; o-methoxy; p-methoxy; o-methyl; m-trifluoromethoxy; m-trifluoromethyl-p-chloro; 2,5-dichloro; 3-chloro-4-fluoro; 2-fluoro-3-chloro; or o-trifluoromethyl.

Some example compounds of formula (XII) are provided in Table 12 below.

TABLE 12 Example Compounds of Formula (XII) Compound R₁ 2304 H 3118 m-chloro 3119 3,4-dichloro 3120 o-methoxy 3121 p-methoxy 3122 o-methyl 3123 m-trifluoromethoxy 3124 m-trifluoromethyl-p-chloro 3126 2,5-dichloro 3127 3-chloro-4-fluoro 3128 2-fluoro-3-chloro 3129 o-trifluoromethyl

Referring now to FIG. 24 , compounds consistent with formula (XII) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XII) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XII). Intermediates 11_(XII) can be formed by alkylating R₁-substituted anilines 10_(XII) with N-(β-haloethyl)-N′-methylpiperazines 12_(XII) in the presence of base. Combining intermediates 11_(XII) with intermediates 9_(XII) in the presence of base yields compounds of formula (XII).

In other embodiments, the present disclosure provides a compound of formula (XIII):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XIII) are provided in Table 13 below.

TABLE 13 Example Compounds of Formula (XIII) Compound R₈ 3130 —NH₂ 3131 —NH(Me) 2290 —N(Me)₂ 2303

2304

Referring now to FIG. 25 , compounds consistent with formula (XIII) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XIII) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XIII). Intermediates 11_(XIII) can be formed by alkylating aniline 10_(XIII) with p-R₈-substituted-α-haloethanes 12_(XIII) in the presence of base. Combining intermediates 11_(XIII) with intermediates 9_(XIII) in the presence of base yields compounds of formula (XIII).

In other embodiments, the present disclosure provides a compound of formula (XIV):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XIV) are provided in Table 14 below.

TABLE 14 Example Compounds of Formula (XIV) Compound R₈ 3135 —NH₂ 3136 —NH(Me) 2291 —N(Me)₂ 3138

3139

Referring now to FIG. 26 , compounds consistent with formula (XIV) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XIV) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XIV). Intermediates 11_(XIV) can be formed by alkylating m-chloroaniline 10_(XIV) with p-R₈-substituted-α-haloethanes 12_(XIV) in the presence of base. Combining intermediates 11_(XIV) with intermediates 9_(XIV) in the presence of base yields compounds of formula (XIV).

In other embodiments, the present disclosure provides a compound of formula (XV):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XV) are provided in Table 15 below.

TABLE 15 Example Compounds of Formula (XV) Compound R₈ 3140 —NH₂ 3141 —NH(Me) 2292 —N(Me)₂ 3143

3144

Referring now to FIG. 27 , compounds consistent with formula (XV) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XV) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XV). Intermediates 11_(XV) can be formed by alkylating 3,4-dichloroaniline 10_(XV) with p-R₈-substituted-α-haloethanes 12_(XV) in the presence of base. Combining intermediates 11_(XV) with intermediates 9_(XV) in the presence of base yields compounds of formula (XV).

In other embodiments, the present disclosure provides a compound of formula (XVI):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XVI) are provided in Table 16 below.

TABLE 16 Example Compounds of Formula (XVI) Compound R₈ 3145 —NH₂ 3146 —NH(Me) 2293 —N(Me)₂ 3148

3149

Referring now to FIG. 28 , compounds consistent with formula (XVI) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XVI) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XVI). Intermediates 11_(XVI) can be formed by alkylating o-methoxyaniline 10_(XVI) with p-R₈-substituted-α-haloethanes 12_(XVI) in the presence of base. Combining intermediates 11_(XVI) with intermediates 9_(XVI) in the presence of base yields compounds of formula (XVI).

In other embodiments, the present disclosure provides a compound of formula (XVII):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XVII) are provided in Table 17 below.

TABLE 17 Example Compounds of Formula (XVII) Compound R₈ 3150 —NH₂ 3151 —NH(Me) 2294 —N(Me)₂ 3153

3154

Referring now to FIG. 29 , compounds consistent with formula (XVII) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XVII) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XVII). Intermediates 11_(XVII) can be formed by alkylating p-methoxyaniline 10_(XVII) with p-R₈-substituted-α-haloethanes 12_(XVII) in the presence of base. Combining intermediates 11_(XVII) with intermediates 9_(XVII) in the presence of base yields compounds of formula (XVII).

In other embodiments, the present disclosure provides a compound of formula (XVIII):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XVIII) are provided in Table 18 below.

TABLE 18 Example Compounds of Formula (XVIII) Compound R₈ 3155 —NH₂ 3156 —NH(Me) 2295 —N(Me)₂ 3158

3159

Referring now to FIG. 30 , compounds consistent with formula (XVIII) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XVIII) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XVIII). Intermediates 11_(XVIII) can be formed by alkylating o-methylaniline 10_(XVIII) (also referred to as o-toluidine or 2-aminotoluene) with p-R₈-substituted-α-haloethanes 12_(XVIII) in the presence of base. Combining intermediates 11_(XVIII) with intermediates 9_(XVIII) in the presence of base yields compounds of formula (XVIII).

In other embodiments, the present disclosure provides a compound of formula (XIX):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XIX) are provided in Table 19 below.

TABLE 19 Example Compounds of Formula (XIX) Compound R₈ 3160 —NH₂ 3161 —NH(Me) 2296 —N(Me)₂ 3163

3164

Referring now to FIG. 31 , compounds consistent with formula (XIX) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XVX) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XVX). Intermediates 11_(XVX) can be formed by alkylating 3-trifluoromethoxyaniline 10_(XVX) with p-R₈-substituted-α-haloethanes 12_(XVX) in the presence of base. Combining intermediates 11_(XVX) with intermediates 9_(XVX) in the presence of base yields compounds of formula (XIX).

In other embodiments, the present disclosure provides a compound of formula (XX):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XX) are provided in Table 20 below.

TABLE 20 Example Compounds of Formula (XX) Compound R₈ 3165 —NH₂ 3166 —NH(Me) 2297 —N(Me)₂ 3168

3169

Referring now to FIG. 32 , compounds consistent with formula (XX) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XX) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XX). Intermediates 11_(XX) can be formed by alkylating 4-chloro-3-trifluoromethylaniline 10_(XX) with p-R₈-substituted-α-haloethanes 12_(XX) in the presence of base. Combining intermediates 11_(XX) with intermediates 9_(XX) in the presence of base yields compounds of formula (XX).

In other embodiments, the present disclosure provides a compound of formula (XXI):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XXI) are provided in Table 21 below.

TABLE 21 Example Compounds of Formula (XXI) Compound R₈ 3170 —NH₂ 3171 —NH(Me) 2298 —N(Me)₂ 3173

3174

Referring now to FIG. 33 , compounds consistent with formula (XXI) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XXI) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XXI). Intermediates 11_(XXI) can be formed by alkylating 2,5-dichloroaniline 10_(XXI) with p-R₈-substituted-α-haloethanes 12_(XXI) in the presence of base. Combining intermediates 11_(XXI), with intermediates 9_(XXI) in the presence of base yields compounds of formula (XXI).

In other embodiments, the present disclosure provides a compound of formula (XXII):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XXII) are provided in Table 22 below.

TABLE 22 Example Compounds of Formula (XXII) Compound R₈ 3175 —NH₂ 3176 —NH(Me) 2299 —N(Me)₂ 31783

3179

Referring now to FIG. 34 , compounds consistent with formula (XXII) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XXII) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XXII). Intermediates 11_(XXII) can be formed by alkylating 3-chloro-4-fluoroaniline 10_(XXII) with p-R₈-substituted-α-haloethanes 12_(XXII) in the presence of base. Combining intermediates 11_(XXII) with intermediates 9_(XXII) in the presence of base yields compounds of formula (XXII).

In other embodiments, the present disclosure provides a compound of formula (XXIII):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XXIII) are provided in Table 23 below.

TABLE 23 Example Compounds of Formula (XXIII) Compound R₈ 3180 —NH₂ 3181 —NH(Me) 2300 —N(Me)₂ 3183

3184

Referring now to FIG. 35 , compounds consistent with formula (XXIII) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XXIII) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XXIII). Intermediates 11_(XXIII) can be formed by alkylating 3-chloro-2-fluoroaniline 10_(XXIII) with p-R₈-substituted-α-haloethanes 12_(XXIII) in the presence of base. Combining intermediates 11_(XXIII) with intermediates 9_(XXIII) in the presence of base yields compounds of formula (XXIII).

In other embodiments, the present disclosure provides a compound of formula (XXIV):

wherein R₈ is selected from the group consisting of: NH₂, NH(Me), N(Me)₂,

Some example compounds of formula (XXIV) are provided in Table 24 below.

TABLE 24 Example Compounds of Formula (XXIV) Compound R₈ 3185 —NH₂ 3186 —NH(Me) 2301 —N(Me)₂ 3188

3189

Referring now to FIG. 36 , compounds consistent with formula (XXIV) can be synthesized by, for example, acylating para-methoxy-N-methylaniline 8_(XXIV) with bromoacetyl bromide to form intermediate N-bromoacetyl-N-methyl-p-methoxyaniline 9_(XXIV). Intermediates 11_(XXIV) can be formed by alkylating 3-chloro-2-fluoroaniline 10_(XXIV) with p-R₈-substituted-α-haloethanes 12_(XXIV) in the presence of base. Combining intermediates 11_(XXIV) with intermediates 9_(XXIV) in the presence of base yields compounds of formula (XXIV).

2. Anesthetic Compositions

The present disclosure provides compositions comprising a compound of any one of formulas (I) to (XXIV). Compositions of the present disclosure may be in any suitable form for delivery to a subject in need thereof, including without limitation topical (cutaneous and transdermal) formulations, injectable (IV, IM, SQ) formulations, intrathecal formulations, oral formulations, sublingual formulations, buccal formulations, otic formulations, ophthalmic formulations, intravesical formulations, rectal formulations, vaginal formulations, inhaled formulations, or nasal formulations.

A) Topical Compositions

Compositions of the present disclosure may be a topical formulation in the form of a lotion, a cream, a gel, a stick, a spray, an ointment, or a paste. In some embodiments, the composition may be applied to skin of the subject using a dispenser. In other embodiments, the composition may be applied to skin of the subject using a dressing, a patch or a pad.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in a topical composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is applied to skin of the subject proximal to the perceived pain or the expected pain. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 5% w/w, in an amount of about 0.05% w/w to about 2% w/w, or in an amount of about 0.1% w/w to about 1% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w.

In some embodiments, the topical composition further comprises a carrier. In some embodiments, the carrier comprises, consists essentially of, or consists of water. In some embodiments, the carrier includes one or more solubilizing agents such as a hydrophobic solvent, an amphipathic solvent, a co-solvent, an emulsifier, a surfactant, etc.

In some embodiments, the topical composition further comprises a penetration enhancer, for example to enhance passage of the compound through skin of the subject. For example and without limitation, a composition of the present disclosure may include a vasodilator.

B) Injectable Formulations

Compositions of the present disclosure may be an injectable formulation in the form of an intravenous formulation, an intramuscular formulation, or a subcutaneous formulation.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an injectable composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is injected in the subject intravenously, intramuscularly, or subcutaneously. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the injectable composition further comprises a solvent system. The solvent system may include one or more solvents. In some embodiments, the solvent system comprises water (e.g., Water for Injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., Water for Injection). In other embodiments, the solvent system comprises water (e.g., Water for Injection) and a cosolvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and/or dimethylsulfoxide.

In some embodiments, the injectable composition further comprises a tonicity agent, such as sodium chloride or sodium sulfite.

In some embodiments, the injectable composition comprises a pH adjuster, such as an acid or a base.

In some embodiments, the injectable composition comprises a buffer system to maintain the pH level of the injectable composition within a desired pH range.

In some embodiments, the injectable composition comprises a non-ionic surfactant, such as Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, mono-fatty acid esters of PEG 300, mono-fatty acid esters of PEG 400, mono-fatty acid esters of PEG 1750, di-fatty acid esters of PEG 300, di-fatty acid esters of PEG 400, and/or di-fatty acid esters of PEG 1750.

In some embodiments, the injectable composition comprises a water-insoluble lipid, such as castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, and/or medium-chain triglycerides of palm seed oil.

In some embodiments, the injectable composition comprises an organic liquid/semi-solid, such as beeswax, D-α-tocopherol, oleic acid, medium-chain monoglycerides, and/or medium-chain diglycerides.

In some embodiments, the injectable composition comprises a cyclodextrin, such as alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and/or sulfobutylether-beta-cyclodextrin.

In some embodiments, the injectable composition comprises a phospholipid, such as hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, and/or L-alpha-dimyristoylphosphatidylglycerol.

C) Intrathecal Formulations

Compositions of the present disclosure may be an intrathecal formulation in the form of a solution suitable for injection into the spinal cord or into the subarachnoid space.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an intrathecal composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is provided to the cerebrospinal fluid of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the intrathecal composition further comprises a solvent system. The solvent system may include one or more solvents. In some embodiments, the solvent system comprises water (e.g., Water for Injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., Water for Injection). In other embodiments, the solvent system comprises water (e.g., Water for Injection) and a cosolvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and/or dimethylsulfoxide.

In some embodiments the osmolality of the intrathecal composition is about 260 mOsm/kg to about 320 mOsm/kg.

In some embodiments, the intrathecal composition further comprises a tonicity agent, such as sodium chloride or sodium sulfite.

In some embodiments, the intrathecal composition comprises a pH adjuster, such as an acid or a base.

In some embodiments, the intrathecal composition comprises a buffer system to maintain the pH level of the intrathecal composition within a desired pH range.

In some embodiments, the intrathecal composition comprises a non-ionic surfactant, such as Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, mono-fatty acid esters of PEG 300, mono-fatty acid esters of PEG 400, mono-fatty acid esters of PEG 1750, di-fatty acid esters of PEG 300, di-fatty acid esters of PEG 400, and/or di-fatty acid esters of PEG 1750.

In some embodiments, the intrathecal composition comprises a water-insoluble lipid, such as castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, and/or medium-chain triglycerides of palm seed oil.

In some embodiments, the intrathecal composition comprises an organic liquids/semi-solid, such as beeswax, D-α-tocopherol, oleic acid, medium-chain monoglycerides, and/or medium-chain diglycerides.

In some embodiments, the intrathecal composition comprises a cyclodextrin, such as alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and/or sulfobutylether-beta-cyclodextrin.

In some embodiments, the intrathecal composition comprises a phospholipid, such as hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, and/or L-alpha-dimyristoylphosphatidylglycerol.

D) Oral Formulations

Compositions of the present disclosure may be an oral dosage formulation in the form of a capsule, lozenge, syrup, solution, elixir, emulsion, tincture, decoction, tablet, thin film, or powder.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an oral composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is ingested by the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the oral composition comprises an outer coating material, such as a polyvinyl alcohol-based film coating system (e.g., the Opadry Clear Coating system 85F190000 further including talc and PEG). When present, the outer coating material may comprise about 4% w/w to about 14% w/w (e.g., about 4% w/w, about 6% w/w, about 8% w/w, about 10% w/w, about 12% w/w, or about 14% w/w) compared to the weight of the oral composition's other components.

In some embodiments, the oral composition comprises a disintegrant, such as alginic acid (Kelacid™, Protacid™, Satialgine H8™), calcium phosphate, tribasic (Tri-Cafos™, TRI-CAL WG™ TRI-TAB™), carboxymethylcellulose calcium (ECG 505™, Nymcel ZSC™) carboxymethylcellulose sodium (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel Tylose CB™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Cab-O-Si™-5P™, Wacker HDK™), croscarmellose sodium (Ac-Di-Sol™, Explocel™, Nymcel ZSX™, Pharmacel XL™, Primellose™, Solutab™, Vivasol™), crospovidone (Kollidon CL™, Kollidon CL-M™, Polyplasdone XL™ Polyplasdone XL-IO™), docusate sodium, guar gum (Galactosol™, Meprogat™, Meyprodor™ Meyprofin™, Meyproguar™), low substituted hydroxypropyl cellulose, magnesium aluminum silicate (Carrisorb™, Gelsorb™, Magnabite™, Neusilin™, Pharmsorb™, Veegum™) methylcellulose (Benecel™, Culminal MC™, Methocel™, Metolose™), microcrystalline cellulose (Avicel PH™, Celex™, Celphere™, Ceolus KG™, Emcoel™, Ethispheres™, Fibrocel™ Pharmacel™, Tabulose™, Vivapur™), povidone (Kollidon™, Plasdone™) sodium alginate (Kelcosol™, Keltone™, Protanal™), sodium starch glycolate (Explotab™, Primojel™, Vivastar P™) polacrilin potassium (Amberlite IRP88™), silicified microcrystalline cellulose (ProSolV™) starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™) or pre-gelatinized starch (Instanstarch™, Lycatab C™, Lycatab PGS™ Merigel™, National 78-1551™, Pharma-Ge™, Prejel™, Sepistab ST 200™, Spress B820™ Starch 1500 G™, Tablitz™, Unipure LD™ and Unipure WG220™), or mixtures thereof. When present the disintegrant may comprise about 2% w/w to about 16% w/w (e.g., about 2% w/w, about 4% w/w, about 6% w/w, about 8% w/w, about 10% w/w, about 12% w/w, about 14% w/w, or about 16% w/w) of the oral composition's total weight.

In some embodiments, the oral composition comprises a binder, such as acacia, alginic acid (Kelacid™, Protacid™, Satialgine H8™), carbomer (Acritamer™, Carbopol™, Pemulen™ Ultrez™), carboxymethylcellulose sodium (Akucell™, Aquasorb™, Blanose™, Finnfix™, Nymcel™ Tylose™), ceratonia (Meyprofleur™), Cottonseed oil, dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), dextrose (Caridex™, Dextrofm™, Lycedex PF™, Roferose™, Tabfme D-IOO™), gelatin (Cryogel™, Instagel™, Solugel™), guar gum (Galactosol™, Meprogat™ Meyprodor™, Meyprofm™, Meyproguar™), hydrogenated vegetable oil type I (Akofine™ Lubritab™, Sterotex™, Dynasan P[omicron]O™, Softisan 154™, Hydrocote™, Lipovol™, HS-K™, Sterotex HM™), hydroxyethyl cellulose (Alcoramnosan™, Cellosize™, Idroramnosan™ Liporamnosan™, Natrosol™, Tylose PHA™), hydroxyethylmethyl cellulose (Culminal™, Tylopur MH™, Tylopur MHB™, Tylose MB™, Tylose MH™, Tylose MHB™), hydroxypropyl cellulose (Klucel™, Methocel™ Nisso HPC™), low substituted hydroxypropyl cellulose, hypromellose (Benecel MHPC™, Methocel™, Metolose™, Pharmacoat™, Spectracel 6™, Spectracel 15™ Tylopur™), magnesium aluminium silicate (Carrisorb™, Gelsorb™, Magnabite™, Neusilin™ Pharmsorb™, Veegum™), maltodextrin (C*Dry MD™, Glucidex™, Glucodry™, Lycatab DSH™ Maldex™, Maltagran™, Maltrin™, Maltrin QD™, Paselli MD 10 PH™, Star_Dri™) maltose (Advantose 100™) methylcellulose (Benecel™, Culminal MC™, Methocel™, Metolose™) microcrystalline cellulose (Avicel PH™ CelexV™, Celphere™, Ceolus KG™, Emcocel™ Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (Litesse™) polyethylene oxide (Polyox™), polymethacrylates (Eastacryl 30D™, Eudragit™, Kollicoat MAE 30D™, Kollicoat MAE 30DP™), povidone (Kollidon™, Plasdone™), sodium alginate (Kelcosol™ Keltone™, Protanal™), starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™), pregelatinised starch (Instastarch™, Lycatab C™, Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™ Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™, Unipure WG 220™), stearic acid (Crodacid™, Emersol Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), sucrose and zein, or mixtures thereof. When present, the binder may comprise about 0.5% w/w to about 20% w/w (e.g., about 0.5% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/w) of the oral composition's total weight.

In some embodiments, the oral composition comprises a diluent (also referred to as a filler), such as calcium carbonate (Barcroft™, Cal_Carb™, CalciPure™, Destab™, MagGran™, Millicarb™ Pharma-Carb™, Precarb™, Sturcal™, Vivapres Ca™), calcium phosphate, dibasic anhydrous (A-TAB™, Di-Cafos A-N™, Emcompress Anhydrous™, Fujicalin™), calcium phosphate, dibasic dihydrate (Cafos™, Calipharm™, Calstar™, Di_Cafos™, Emcompress™), calcium phosphate tribasic (Tri-Cafos™, TRI-CAL WG™, TRI-TAB™), calcium sulphate (Destab™, Drierite™, Snow White™, Cal-Tab™, Compactrol™, USG Terra Alba™), cellulose powdered (Arbocel™, Elcema™ Sanacel™, Solka-Floc™), silicified microcrystalline cellulose (ProSolV™), cellulose acetate, compressible sugar (Di-Pac™), confectioner's sugar, dextranes (Candex™, Emdex™), dextrin (Avedex™, Caloreen™, Crystal Gum™, Primogran W™), dextrose (Caridex™, Dextrofin™ Lycadex PF™, Roferose™, Tab fine DT-IOO™), fructose (Advantose™, Fructamyl™, Fructofin™ Krystar™), kaolin (Lion™, Sim 90™), lactitol (Finlac ACX™, Finlac DC™, Finlac MCX™), lactose (Aero Flo 20™, Aero Flo 65™, Anhydrox™, CapsuLac™, Fast-Flo™, FlowLac™, GranuLac™ InhaLac™, Lactochem™, Lactohale™, Lactopressr™, Microfine™, Microtose™, Pharmatose™ Prisma Lac™, Respitose™, SacheLac™, SorboLac™, Super-Tab™, Tablettose™, Wyndale™ Zeparox™), magnesium carbonate, magnesium oxide (MagGran MO™), maltodextrin (C*Dry MD™, Glucidex™, Glucodry™, Lycatab DSH™, Maldex™, Maltagran™, Maltrin™, Maltrin QD™ Paselli MD 10 PH™, Star_Dri™), maltose (Advantose 100™), mannitol (Mannogem™, Pearlitol™) microcrystalline cellulose (Avicel PH™, Celex™, Celphere™, Ceolus KG™, Emcocel™ Ethispheres™, Fibrocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (Litesse™) simethicone (Dow Corning Q7-2243 LVA™, Cow Corning Q7-2587™, Sentry Simethicone™) sodium alginate (Kelcosol™, Keltone™, Protanal™), sodium chloride (Alberger™), sorbitol (Liponec 70-NC™, Liponic 76-NCv, Meritol™, Neosorb™, Sorbifin™, Sorbitol Instant™ Sorbogem™), starch (Aytex P™, Fluftex W™, Instant Pure-Cote™, Melojel™, Meritena Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™ Purity 21™, Purity 826™, Tablet White™), pregelatinized starch (Instastarch™, Lycatab C™ Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™ Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™, Unipure WG220™), sucrose, trehalose and xylitol (Klinit™, Xylifm™, Xylitab™, Xylisorb™, Xylitolo™), or mixtures thereof. When present, the diluent may comprise up to about 20% w/w (e.g., about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/w) of the oral composition's total weight.

In some embodiments, the oral composition comprises a lubricant, such as calcium stearate (HyQual™), glycerine monostearate (Capmul GMS-50™, Cutina GMS™, ImwitorTMI91 and 900, Kessco GMS5™ Lipo GMS™ 410, 450 and 600, Myvaplex 600P™, Myvatex™, Protachem GMS-450™, Rita GMS™, Stepan GMS™, Tegin™, Tegin™503 and 515, Tegin 4100™, Tegin M™ Unimate GMS™), glyceryl behenate (Compritol 888 ATO™), glyceryl palmitostearate (Precirol ATO 5™), hydrogenated castor oil (Castorwax™, Castorwax MP 70™, Castorwax MP 80™ Crodure™, Cutina HR™, Fancol™, Simulsol 1293™), hydrogenated vegetable oil type I (Akofine™, Lubritab™, Sterotex™, Dynasan P60™, Softisan 154™, Hydrocote™, Lipovol HS-K™ Sterotex HM™), magnesium lauryl sulphate, magnesium stearate, medium-chain triglycerides (Captex 300™, Captex 355™, Crodamol GTC/C™, Labrafac CC™, Miglyol 810™, Miglyol 812™ Myritol™, Neobee M5™, Nesatol™, Waglinol 3/9280™), poloxamer (Lutrol™, Monolan™ Pluronic™, Synperonic™) polyethylene glycol (Carbowax™, Carbowax Sentry™, Lipo™ Lipoxol™, Lutrol E™, Pluriol E™), sodium benzoate (Antimol™), sodium chloride (Alberger™) sodium lauryl sulphate (Elfan 240™, Texapon K1 2P™), sodium stearyl fumarate (Pruvr™), stearic acid (Crodacid E570™, Emersol™, Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), talc (Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, Magsil Star™, Superiore™) sucrose stearate (Surfhope SE Pharma D-1803 F™) and zinc stearate (HyQual™), or mixtures thereof. When present, the lubricant may comprise about 0.1% w/w to about 6% w/w (e.g., about 0.1% w/w, about 0.25% w/w, about 0.5% w/w, about 0.75% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, or about 6% w/w) of the oral composition's total weight.

In some embodiments, the oral composition comprises a glidant, such as tribasic calcium phosphate (Tri-Cafos™, TRI-CAL™, TRI-TAB™), calcium silicate, cellulose, powdered (Arbocel™, Elcema™, Sanacel™, Solka-Floc™) colloidal silicon dioxide (Aerosil™, Cab-O-Sij™, Cab-O-Sil M-5P™, Wacker HDK™), magnesium silicate, magnesium trisilicate, starch (Aytex P™, Fluftex W™ Instant Pure-Cote™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White™) and talc (Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, Magsil Star™, Superiore™), or mixtures thereof. When present, the glidant may comprise about 0.1% w/w to about 4% w/w (e.g., about 0.1% w/w, about 0.25% w/w, about 0.5% w/w, about 0.75% w/w, about 1% w/w, about 2% w/w, about 3% w/w, or about 4% w/w) of the oral composition's total weight.

In some embodiments, the oral composition further comprises an inner protective barrier coating material, such as a methacrylic acid and ethyl acrylate copolymer system (e.g., Acryl-EZE II), a methacrylic acid, methyl methacrylate (1:1) polymer system (e.g., Eudragit L100), a methacrylic acid, methyl methacrylate (1:2) polymer system (e.g., Eudragit S100), or a hydroxypropylmethylcellulose-based film coating system (e.g., the Opadry Complete film coating system 03B28796 additionally including titanium dioxide and PEG). The protective barrier coating material may be present in an amount of about 1% w/w to about 10% w/w (e.g., about 2% w/w or about 4% w/w) of the oral composition weight.

E) Sublingual Formulations

Compositions of the present disclosure may be a sublingual formulation in the form of a sublingual tablet, sublingual strip, soluble sublingual tablet, sublingual drop, sublingual spray, lozenge, or effervescent sublingual tablet.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in a sublingual composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is absorbed by a mucous membrane of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the sublingual composition is a molded sublingual tablet comprising, in addition to an effective amount of a compound of any one of formulas (I) to (XXIV), an excipient such as lactose, dextrose, sucrose, mannitol, finely divided kaolin, calcium carbonate, calcium phosphate, an antioxidant (e.g., sodium bisulfate), a buffer, glucose, sucrose, acacia, povidone, or mixtures of any two or more of the foregoing.

In some embodiments, the sublingual composition is a compressed sublingual tablet comprising, in addition to an effective amount of a compound of any one of formulas (I) to (XXIV), a disintegrant (e.g., a super disintegrant), a lubricant, microcrystalline cellulose, a dry binder, a buffer system, a surface-active agent, a sweetener, a flavorant, a bulking agent (e.g., a sugar-based bulking agent), a saccharide-based material, an effervescent agent, or a mixture of any two or more of the foregoing.

F) Buccal Formulations

Compositions of the present disclosure may be a buccal formulation in the form of a buccal tablet, such as an effervescent buccal tablet.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in a buccal composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is absorbed by a mucous membrane of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the buccal composition further comprises a penetration enhancer, such as a surfactant (e.g., sodium lauryl sulfate, cetyl pyridinium chloride, poloxamer, Brij, Span, Myrj, or Tween), a bile salt (e.g., sodium glycocholate, sodium tauro deoxycholate, or sodium tauro cholate), a fatty acid (e.g., oleic acid, caprylic acid, lauric acid, lyso phosphatidyl choline, or phosphatidyl choline), a cyclodextrin (e.g., α-cyclodextrin, p-cyclodextrin, γ-cyclodextrin, or methylated p-cyclodextrins), a chelator (e.g., EDTA, citric acid, soldium salicylate, or methoxy salicylate), a positively-charged polymer (e.g., chitosan or trimethyl chitosan), or a cationic compound (e.g., poly-L-arginine or L-lysine).

In some embodiments, the buccal composition further comprises an enzyme inhibitor, such as aprotinin, bestatin, puromycin, some bile salts, polyacrylic acid (e.g., carbomer), a chitosan derivative (e.g., chitosan-EDTA), a thiol derivative of polyacrylate, or a thiol derivative of chitosan.

In some embodiments, the buccal composition further comprises a solubility modifier, such as a cyclodextrin (e.g., hydroxylpropyl-p-cyclodextrin) or hydroxylpropyl methyl cellulose.

In some embodiments, the buccal composition further comprises an acid to promote intercellular (paracellular) transport of the compound of formula (I) to (XXIV) across buccal mucosa.

In some embodiments, the buccal composition further comprises a mucoadhesive polymer, such as agarose, chitosan, gelatin, hyaluronic acid, guar gum, hakea gum, xanthan gum, gellan, carragenan, pectin, sodium alginate, a cellulose derivative (e.g., CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, or MC), a poly(acrylic acid)-based polymer (e.g., CP, PC, PAA, or a copolymer of acrylic acid and PEG), PVA, PVP, a thiolated polymer (e.g., a thiolated polyacrylates, thiolated chitosan, or deacetylated gellan gum), aminodextran, dimethylaminoethyl (DEAE)-dextran, trimethylated chitosan, chitosan-EDTA, hydroxyethyl starch, poly(ethylene oxide), scleroglucan, cyanoacrylate, a lectin, or a bacterial adhesive agent.

G) Otic Formulations

Compositions of the present disclosure may be an otic formulation in the form of a solution, a suspension, an emulsions, a drop, or a spray.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an otic composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the otic composition further comprises a pH modifier, such as acetic acid, calcium carbonate, citric acid, hydrochloric acid, benzethonium chloride, benzyl alcohol, hydrochloric acid, lactic acid, monopotassium phosphate, sodium acetate, sodium borate, sodium citrate, dibasic sodium phosphate, monobasic sodium diphosphate, sodium hydroxide, sulfuric acid, or tromethamine.

In some embodiments, the otic composition further comprises an antimicrobial preservative, such as aluminum acetate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, boric acid, chlorobutanol, isopropyl alcohol, phenethyl alcohol, methylparaben, potassium metabisulfate, propylparaben, or thiomersal.

In some embodiments, the otic composition further comprises a suspension agent, such as aluminum sulfate, cetyl alcohol, hydroxyethyl cellulose, methylparaben, or polyvinyl alcohol.

In some embodiments, the otic composition further comprises a stabilizing agent, such as creatinine, hydrogenated soybean lecithin, povidone K30, povidone K90, or poloxamer 407.

In some embodiments, the otic composition further comprises an emollient, such as cupric sulfate, glycerol, or polyoxyl 40 stearate.

In some embodiments, the otic composition further comprises a solubilizer, such as polysorbate 20, polysorbate 80, or tyloxapol.

In some embodiments, the otic composition further comprises a tonicity agent, such as sodium chloride or sodium sulfite.

In some embodiments, the otic composition further comprises an ointment base, such as mineral oil, peanut oil, or petrolatum.

H) Ophthalmic Formulations

Compositions of the present disclosure may be an ophthalmic formulation in the form of an eye drop, an ointment, an in situ gel, an insert, a multicompartment drug delivery system, or a bioadhesive formulation.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an ophthalmic composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the ophthalmic composition further comprises a solvent system. The solvent system may include one or more solvents. In some embodiments, the solvent system comprises water (e.g., Water for Injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., Water for Injection). In other embodiments, the solvent system comprises water (e.g., Water for Injection) and a cosolvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and/or dimethylsulfoxide.

In some embodiments, the ophthalmic composition further comprises a preservative, such as benzyl alcohol.

In some embodiments, the ophthalmic composition further comprises a buffer system configured to maintain the pH level of the composition within a range of about 4 to about 8 (e.g., about 7.4). In some embodiments, the ophthalmic composition further comprises a viscosity agent to maintain the viscosity of the composition within a range of about 15 mPas to about 150 mPas. When present, the viscosity agent may optionally be a polyvinyl alcohol, a poloxamer (e.g., poloxamer 407), hyaluronic acid, a carbomer, a polysaccharide (e.g., a cellulose derivative, gellan gum, or xanthan gum).

In some embodiments, the ophthalmic composition further comprises a penetration enhancer, such as a chelating agent, a preservative (e.g., benzalkonium chloride), a surfactant, or a bile acid salt. When present, the penetration enhancer should be included in an amount sufficient to improve bioavailability of the compound of any one of formulas (I) to (XXIV) (e.g., in the aqueous humor) without inducing irritation or local tissue toxicity.

In some embodiments, the ophthalmic composition further comprises a solubilizer, such as a cyclodextrin (e.g., 2-hydroxypropyl-p-cyclodextrin). When present, the solubilizer may comprise about 1% w/w to about 15% w/w (e.g., about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w) of the total weight of the composition.

I) Intravesical Formulations

Compositions of the present disclosure may be an intravesical formulation in the form of a nanoparticle, a hydrogel, a dendrimer, or a liposome.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an intravesical composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the intravesical composition further comprises a mucoadhesive system, such as a polymer capable of interacting with urothelial glycosaminoglycans.

In some embodiments, the intravesical composition further comprises a viscosity enhancer, such as a thermo-sensitive polymer having a relatively low viscosity at low temperature and a gel-like consistency at relatively higher temperature (e.g., TCGel®).

In some embodiments, the intravesical composition further comprises an effervescent (e.g., CO₂- or gas-generating) agent, such as sodium bicarbonate, ammonium bicarbonate, or perfluoro pentane.

In some embodiments, the intravesical composition is housed within an intravesical drug reservoir having a pressure responsive valve (e.g., a UROS infusor, Situs Corp.).

In some embodiments, the intravesical composition is housed within an intravesical balloon, which is delivered to the bladder via magnetic or other control device.

In some embodiments, the intravesical composition is housed within a microsphere matrix (e.g., polydimethylsiloxane microspheres), optionally bound together by resorbable suture threads. In such embodiments, the microspheres may be provided to the bladder where the compound of formula (I) to (XXIV) elutes from the microsphere matrix.

In some embodiments, the intravesical composition is housed within a silicon tube, such as a retentive silicon tube-nitinol wire device, that is provided to the bladder (e.g., by catheter) whereafter the compound of formula (I) to (XXIV) elutes from the silicon tube.

In some embodiments, the intravesical composition is housed within a biodegradable elastomer-based device including an osmotic release mechanism. Upon delivery of the device to the bladder, the compound of formula (I) to (XXIV) elutes by osmosis and diffusion.

In some embodiments, the intravesical composition is housed within a U- or helix-shaped PVA matrix. Upon delivery of the PVA matrix to the bladder, the compound of any one of formulas (I) to (XXIV) elutes.

J) Rectal Formulations

Compositions of the present disclosure may be a rectal formulation in the form of a suppository or an enema.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in a rectal composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the rectal composition is a suppository and further comprises an excipient system configured to melt at body temperature. In some embodiments, the excipient system comprises an oleaginous base (e.g., cocoa butter, emulsified cocoa butter, hydrogenated oils), a hydrophilic base (e.g., glycerol-gelatin base, soap-glycerine base, or a PEG), an emulsifying base (e.g., Witepsol, massa estarinum, or massuppol).

In some embodiments, the rectal composition is an enema and further comprises a solvent system. The solvent system may include one or more solvents. In some embodiments, the solvent system comprises water (e.g., Water for Injection). In some embodiments, the solvent system comprises, consists essentially of, or consists of water (e.g., Water for Injection). In other embodiments, the solvent system comprises water (e.g., Water for Injection) and a cosolvent, such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and/or dimethylsulfoxide. In some embodiments, the enema composition further comprises a tonicity agent, such as sodium chloride or sodium sulfite.

K) Vaginal Formulations

Compositions of the present disclosure may be a vaginal formulation in the form of a hydrogel, a vaginal tablet, a pessary, a suppository, a particulate system, or an intra-vaginal ring.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in a vaginal composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the vaginal composition is a hydrogel and further comprises a vehicle, a gelling agent, a humectant, a preservative, and/or a mucoadhesive agent (e.g., hydroxypropylmethyl cellulose).

In some embodiments, the vaginal composition is a pessary and further comprises one or more of: lactose monohydrate, microcrystalline cellulose, lactic acid, maize starch, crospovidone, calcium lactate pentahydrate, magnesium stearate, colloidal anhydrous silica and/or Hypromellose.

In some embodiments, the vaginal composition is a vaginal tablet and further comprises one or more of: a diluent, a binder, a disintegrant, a glidant, a lubricant, and/or an antiadherant.

In some embodiments, the vaginal composition is a particulate system further comprising a polymer matrix in which the compound of any one of formulas (I) to (XXIV) is included. In some embodiments, the matrix comprises a natural polymer such as a polysaccharide, zein, glutein, collagen, gelatin, albumin, or elastin. In some embodiments, the matrix comprises a synthetic biodegradable polymer such as poly(DL-lactic acid), poly(lactic-co-glycolic acid), polycaprolactone, polyacrylates, polymethacrylates, cellulose derivatives, triblock copolymers of poly(ethylene oxide)/poly(propylene oxide) or poloxamers), poly(vinyl alcohol), poly(ethylene glycol), or alginate. In some embodiments, the matrix comprises a synthetic non-biodegradable polymer such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (Eudragit® RS 100).

In some embodiments, the vaginal composition is housed in an intravaginal ring matrix comprising polyurethane, ethylene vinyl acetate, silicone, acacia gum, or a copolymer of 2-hydroxyethyl methacrylate and sodium methacrylate.

L) Inhaled Formulations

Compositions of the present disclosure may be an inhaled formulation in the form of a dry powder, an aerosol, or a nebulizable solution.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in an inhalable composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the inhalable composition is a dry powder and further comprises an amino acid, a sugar, a stabilizer, a surfactant, and/or a lipid.

In some embodiments, the inhalable composition is an aerosol and further comprises a propellant, a saccharide (e.g., lactose), and/or a co-solvent.

In some embodiments, the inhalable composition is a nebulizable solution further comprising a solvent (e.g., water), a pH adjuster, a buffer system, a starch, a chelator, an emulsifier, a viscosity agent, a tonicity agent, and/or a surfactant.

M) Nasal Formulations

Compositions of the present disclosure may be a nasal formulation in the form of an aqueous solution, an oil, a suspension, an emulsion, or a dry powder.

In some embodiments, the compound of any one of formulas (I) to (XXIV) is present in a nasal composition in an amount effective to treat perceived pain or to prevent expected pain in a subject after the composition is administered to an ear canal of the subject. In some embodiments, the compound is present in an amount of about 0.01% w/w to about 10% w/w, in an amount of about 0.1% w/w to about 8% w/w, in an amount of about 1% w/w to about 6% w/w, or in an amount of about 2% w/w to about 5% w/w. In some embodiments, the compound is present in an amount of about 0.01% w/w, about 0.02% w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.1% w/w, about 0.15% w/w, about 0.2% w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w, about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, or about 10 w/w %.

In some embodiments, the nasal composition is an aqueous solution and further comprises a solvent (e.g., water), a pH adjuster, a buffer system, a starch, a chelator, an emulsifier, a viscosity agent, a tonicity agent, and/or a surfactant.

In some embodiments, the nasal composition is an oil and further comprises a solvent (e.g., a hydrophobic liquid), a pH adjuster, a buffer system, a starch, a chelator, an emulsifier, a viscosity agent, a tonicity agent, and/or a surfactant.

In some embodiments, the nasal composition is a suspension and further comprises a solvent (e.g., water), a pH adjuster, a buffer system, a starch, a chelator, an emulsifier, a viscosity agent, a tonicity agent, and/or a surfactant. In some embodiments, the nasal composition is an emulsion and further comprises a solvent (e.g., water), a pH adjuster, a buffer system, a starch, a chelator, an emulsifier, a viscosity agent, a tonicity agent, and/or a surfactant.

In some embodiments, the nasal composition is a dry powder and further comprises an amino acid, a sugar, a stabilizer, a surfactant, and/or a lipid.

3. Methods of Treating or Preventing Pain

The present disclosure provides methods of treating or preventing pain in a subject. Generally, methods consistent with the present disclosure comprise administering a composition comprising an effective amount of a compound of any one of formulas (I) to (XXIV) to a subject experiencing pain symptoms or expected to experience pain symptoms.

In some embodiments, the method comprises topically applying a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to tissue (e.g., skin) of the subject. In some embodiments, the step of topically applying the composition occurs after the subject observes a pain sensation, and the composition is applied to tissue proximal to the observed pain sensation. In other embodiments, the step of topically applying the composition occurs before the subject observes a pain sensation, and the composition is applied to tissue proximal to a location where a pain sensation is expected to be observed by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject by injecting the composition intravenously, intramuscularly, or subcutaneously. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is injected proximal to the observed pain sensation. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is injected proximal to a location where a pain sensation is expected to be observed by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject by injecting the composition intrathecally, such as into the spinal cord or into the subarachnoid space of the subject. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is injected intrathecally proximal to the observed pain sensation. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is injected intrathecally proximal to a location where a pain sensation is expected to be observed by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject orally. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered orally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered orally to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject sublingually. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered sublingually to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered sublingually to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject buccally. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered bucally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered bucally to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject optically. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered to an ear canal of the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered to an ear canal of the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to one or both eyes of the subject. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered to one or both eyes of the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered to one or both eyes of the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject intravesically. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered into the bladder of the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered into the bladder of the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject rectally. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered rectally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered rectally to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject vaginally. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered vaginally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered vaginally to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject via inhalation pathway. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered via inhalation pathway to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered via inhalation pathway to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

In some embodiments, the method comprises administering a composition of the present disclosure including a compound of any one of formulas (I) to (XXIV) to the subject nasally. In some embodiments, the step of administering the composition occurs after the subject observes a pain sensation, and the composition is administered nasally to the subject to reduce or eliminate the observed pain. In other embodiments, the step of administering the composition occurs before the subject observes a pain sensation, and the composition is administered nasally to the subject to avoid altogether or reduce the severity of pain to be experienced by the subject.

EXAMPLES Example 1. Patch Clamp Testing

An examination of the in vitro effects of the compounds consistent with the present disclosure on ion channels Na_(V)1.5 (a sodium voltage-gated channel alpha subunit found predominantly in cardiac muscle cells) and Na_(V)1.7 (a sodium voltage-gated channel alpha subunit normally expressed in high levels in nociceptive pain neurons at dorsal root ganglion (DRG) and trigeminal ganglion and in sympathetic ganglion neurons) was performed using adult epithelial (ovarian) tissue CHO cells of Chinese hamsters (C. griseus) transformed with adenovirus 5 DNA and transfected with human ion channel cDNAs (ATCC, Manassas, Va.; ChanTest Corp., Cleveland, Ohio). Cells were cultured in Ham's F-12 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, and 500 μg/mL G418 aminoglycoside antibiotic.

Each compound was analyzed at concentrations of 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM. Lidocaine was included as a positive control at concentrations of 3000 μM, 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, and 1 μM. All tested compound formulations contained 0.3% DMSO. Each concentration of each compound was loaded into a well of a 384-well polypropylene compound plate using an automated liquid handling system (Integra Assist Plus, Integra) and then placed in the plate well of SyncroPatch 384PE (SP384PE; Nanion Technologies, Livingston, N.J.) immediately before application of the cells.

Observed IC₅₀ values of the channel current inhibition for each test article are provided in Table 25 (Na_(V)1.5 ion channel inhibition) and Table 26 (Na_(V)1.7 ion channel inhibition).

TABLE 25 Inhibition of Na_(v)1.5 Ion Channel IC₅₀, μM Compound TP1A TP2A TP25B 2290 >1000 >1000 >1000 2291 808.5 740.3 692.5 2292 207.7 215.7 193.1 2293 >1000 >1000 >1000 2294 >1000 >1000 >1000 2295 >1000 >1000 >1000 2296 254.4 235.9 221.6 2297 95.1 91.2 72.7 2298 249.4 240.3 204.0 2299 515.2 449.0 504.5 2300 327.2 307.0 259.2 2301 265.3 242.5 154.0 2302 124.1 96.8 75.9 2303 16.6 13.5 9.5 2304 >1000 880.4 670.2 Lidocaine 453.2 15.8 68.7 (pos. control) TP1A = Tonic Block TP2A = Inactivated State-Dependent Block TP25B = Use-Dependent Block

TABLE 26 Inhibition of Na_(v)1.7 Ion Channel IC₅₀, μM Compound TP1A TP2A TP25B 2290 >1000 >1000 >1000 2291 561.4 463.1 490.4 2292 164.8 162.1 166.5 2293 >1000 >1000 >1000 2294 >1000 >1000 >1000 2295 >1000 >1000 >1000 2296 265.4 231.2 210.5 2297 74.7 66.2 54.4 2298 272.5 228.6 220.5 2299 392.6 315.0 334.3 2300 546.4 672.8 625.8 2301 312.1 275.3 235.0 2302 70.2 77.9 55.4 2303 15.0 14.5 13.1 2304 >1000 >1000 >1000 Lidocaine 407.8 23.7 112.7 (pos. control) TP1A = Tonic Block TP2A = Inactivated State-Dependent Block TP25B = Use-Dependent Block 

1-31. (canceled) 32: A compound of formula (Villa):

wherein: R₂=H or Me; R₃=H or Me; R₄=Alkyl; R₅=O-Alkyl; and Alkyl=aliphatic C₁-C₄ alkyl. 33-64. (canceled) 65: A composition comprising a compound of claim
 32. 66: The composition of claim 65, wherein the composition is for topical administration and further comprises a carrier. 67: The composition of claim 65, wherein the compound is present in an amount sufficient to treat perceived pain or prevent expected pain in a subject after the composition is applied to skin of the subject proximal to the perceived pain or the expected pain. 68: A method of treating or preventing pain in a subject, the method comprising administering the composition of claim 65 to the subject. 69: The method of claim 68, wherein the composition is administered to the subject proximal to perceived pain or expected pain. 70: The compound of claim 32, wherein: R₂=H; and R₃=H. 71: The compound of claim 32, wherein: R₂=Me; and R₃=Me. 72: The compound of claim 32, wherein R₄ is methyl. 73: The compound of claim 32, wherein R₅ is methoxy. 74: The compound of claim 32, wherein each Alkyl is methyl. 75: A method of treating or preventing pain in a subject, the method comprising administering a composition comprising an effective amount of the compound of claim 32 to the subject. 76: A method of treating or preventing pain in a subject, the method comprising administering a composition comprising an effective amount of the compound of claim 70 to the subject. 77: A method of treating or preventing pain in a subject, the method comprising administering a composition comprising an effective amount of the compound of claim 71 to the subject. 78: A method of treating or preventing pain in a subject, the method comprising administering a composition comprising an effective amount of the compound of claim 72 to the subject. 79: A method of treating or preventing pain in a subject, the method comprising administering a composition comprising an effective amount of the compound of claim 73 to the subject. 80: A method of treating or preventing pain in a subject, the method comprising administering a composition comprising an effective amount of the compound of claim 74 to the subject. 